Feasibility Study of a Pre-hospital Extra-corporeal Membrane Oxygenation (ECMO) Capable Advanced Resuscitation Team at Achieving Blood Flow Within 30 Minutes in Patients With Refractory Cardiac Arrest.
Phase: NA
Conditions: Death, Sudden, Cardiac, Out-Of-Hospital Cardiac Arrest, Ventricular Fibrillation, Cardiopulmonary Arrest With Successful Resuscitation
Sponsor: Barts & The London NHS Trust

                                  
 
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JRMO Research Protocol for Interventional Studies 
 
Full Title  
Feasibility study of a pre-hospital extra-corporeal membrane 
oxygenation (ECMO) capable advanced resuscitation team 
at achieving blood flow within 30 minutes in patients with 
refractory cardiac arrest. 
 
Short title 
The Sub30 feasibility trial 
 
Version 
5.0 
 
Version date 
02 Mar 2022 
 
Sponsor 
Barts Health NHS Trust  
 
 
Contact person: 
 
 
Dr Mays Jawad 
 
Trust headquarters Executive Offices 
 
Ground Floor Pathology & Pharmacy Building 
 
The Royal London Hospital 
 
80, Newark Street 
 
London 
 
E1 2ES 
 
Phone: 020 7882 7275 / 6574 
 
Email: research.governance@qmul.ac.uk 
 
IRAS Number 
244748 
 
Sponsor (ReDA) Number 
012543 
 
REC Reference 
19/LO/0035 
 
ClinicalTrials.gov identifier NCT03700125 
 
Chief Investigator 
Dr Simon Finney 
 
Consultant in Intensive Care Medicine 
 
St Bartholomew's Hospital 
 
West Smithfield 
 
London EC1A 7BE 
 
Email: simon.finney2@nhs.net 
 
List of sites 
Barts Health NHS Trust 
 
London Ambulance Service NHS Trust 
 

                                  
 
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Principal Investigator: 
Dr Ben Singer 
 
(Barts Health) 
Consultant in Intensive Care and Anaesthesia 
 
St Bartholomew's Hospital, London 
 
Email: b.singer@nhs.net 
 
 
Principal Investigator: 
Dr Fenella Wrigley 
(London Ambulance Service) Medical Director 
 
London Ambulance Service, UK 
 
fenella.wrigley@lond-amb.nhs.uk 
 
Co-investigators: 
Dr Alastair G Proudfoot 
 
Consultant in Intensive Care and Anaesthesia 
 
St Bartholomew's Hospital, London 
 
alastair.proudfoot1@nhs.net 
 
 
 
Professor Ben O'Brien 
 
Consultant in Intensive Care and Anaesthesia 
 
St Bartholomew's Hospital, London 
 
ben.obrien@nhs.net 
 
 
 
Dr Gareth E Davies 
 
Consultant in Emergency Medicine 
 
London's Air Ambulance, London 
 
gareth.davies5@nhs.net 
 
  
 
Dr Joshua C Reynolds 
 
Assistant Professor of Emergency Medicine 
 
Michigan State University, USA 
 
reyno406@msu.edu 
 
 
 Professor Anthony Mathur 
 
Consultant Interventional Cardiologist 
 
St Bartholomew's Hospital, London 
 
 
a.mathur@qmul.ac.uk 
 
 
 
Mr Mark Whitbread 
 
Consultant Paramedic Resuscitation/Critical Care 
 
London Ambulance Service, UK 
 
mark.whitbread@lond-amb.nhs.uk 
 
 
 
Dr Tom Evens 
 
Consultant in Pre-hospital medicine 
 
London’s Air Ambulance 
 
tomevens@doctors.org.uk 
 
 
Dr Vivienne Monk 
 
Clinical Research Centre Manage 
 
Cardiovascular Clinical Trials Unit 
 
v.monk@qmul.ac.uk 
 
Trial Statistician 
Thomas Godec 
 
Senior Statistician 
 
WHRI, Queen Mary University London 
 
t.godec@qmul.ac.uk 
 

                                  
 
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Trial Pharmacist 
Ian Rowlands 
 
Lead Pharmacist for Critical Care 
 
St Bartholomew’s Hospital, London 
 
i.rowlands@nhs.net 
 
 
List of laboratories 
Barts Health NHS Trust Laboratories 
 
Trial Oversight 
Barts Cardiovascular Clinical Trials Unit (CVCTU) 
 
William Harvey Research Institute 
 
Queen Mary University of London 
 

                                  
 
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Contents 
1. 
Glossary and abbreviations ..................................................................................................... 6 
2. 
Signature page ........................................................................................................................ 7 
3. 
Summary and synopsis ........................................................................................................... 8 
4. 
Introduction ............................................................................................................................. 9 
4.1 
Out of hospital cardiac arrest – the healthcare need ....................................................... 9 
4.2 
Rationale for pre-hospital ECPR ...................................................................................... 9 
4.2.1 
ECPR may improve outcome in refractory cardiac arrest .......................................... 9 
4.2.2 
Pre-hospital institution of ECPR may be the best model of care .............................. 10 
4.3 
Current UK clinical practice for OHCA ........................................................................... 10 
4.4 
Other current and planned studies of ECPR in patients suffering OHCA ...................... 10 
4.5 
Rationale for the Sub30 study ........................................................................................ 11 
4.6 
Risks / benefits ............................................................................................................... 12 
5. 
Study objectives .................................................................................................................... 12 
5.1 
Primary objective ............................................................................................................ 12 
5.2 
Secondary objectives ..................................................................................................... 13 
5.3 
Primary outcome ............................................................................................................ 13 
5.4 
Secondary outcomes ..................................................................................................... 13 
6. 
Study population ................................................................................................................... 13 
6.1 
Inclusion criteria ............................................................................................................. 13 
6.2 
Exclusion criteria ............................................................................................................ 14 
7. 
Study design ......................................................................................................................... 14 
7.1 
Overall design ................................................................................................................ 14 
7.2 
Setting and timescale ..................................................................................................... 14 
7.3 
Timescale ....................................................................................................................... 14 
7.4 
Patient identification / ECPR Team activation ................................................................ 14 
7.5 
Consent waiver at enrolment ......................................................................................... 15 
7.6 
Consent to on-going inclusion in the study .................................................................... 15 
7.7 
Provision of public information about the study .............................................................. 15 
7.8 
Co-enrolment in other clinical studies ............................................................................ 16 
7.9 
End of study ................................................................................................................... 16 
7.10 Study Scheme Diagram ................................................................................................. 17 
8. 
Study procedures .................................................................................................................. 17 
8.1 
ECPR Team members ................................................................................................... 18 
8.2 
Primary assessment ....................................................................................................... 18 
8.3 
ECPR Pre-hospital team roles and responsibilities ........................................................ 18 
8.4 
ECMO consultants’ initial roles and responsibilities ....................................................... 18 
8.5 
Twenty minute time-out if patients remains in cardiac arrest ......................................... 19 
8.6 
ECMO support ............................................................................................................... 19 
8.7 
Transfer to the Heart Attack Centre at St Bartholomew’s Hospital ................................ 19 
8.8 
Post-resuscitation care ................................................................................................... 19 
8.9 
Schedule of assessments .............................................................................................. 20 
8.10 Standard Operating Procedures .................................................................................... 20 
9. 
Assessment and management of risk ................................................................................... 21 
10. Statistical considerations ....................................................................................................... 25 
10.1 Sample size .................................................................................................................... 25 
10.2 Methods of Analysis ....................................................................................................... 25 
11. Ethical and regulatory considerations ................................................................................... 25 
11.1 Protocol .......................................................................................................................... 25 
11.2 Peer review .................................................................................................................... 25 
11.3 Management of actual and potential conflicts of interest ............................................... 25 
11.4 Summary of main ethical, legal and management issues .............................................. 25 

                                  
 
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11.5 Research Ethics Committee (REC) review and reports ................................................. 27 
11.6 Annual Safety Reporting ................................................................................................ 28 
12. Public Involvement ................................................................................................................ 28 
13. Data handling and record keeping ........................................................................................ 28 
13.1 Data management .......................................................................................................... 28 
13.2 Source data .................................................................................................................... 28 
13.3 Confidentiality ................................................................................................................. 29 
13.4 Record Retention and Archiving .................................................................................... 29 
14. Laboratories .......................................................................................................................... 29 
14.1 Central and local laboratories ........................................................................................ 29 
14.2 Sample collection, preparation and procedures ............................................................. 30 
14.3 Sample storage and transfer .......................................................................................... 30 
15. Interventions and tools .......................................................................................................... 30 
15.1 Devices .......................................................................................................................... 30 
15.2 Techniques and interventions ........................................................................................ 30 
15.3 Tools .............................................................................................................................. 31 
15.3.1 EQ-5D-5L ................................................................................................................. 31 
15.3.2 Modified Rankin Scale of neurological assessment ................................................. 31 
15.3.3 Functional independence measure .......................................................................... 31 
15.4 Non-investigational medicinal products (NIMPs) ........................................................... 31 
16. Safety reporting ..................................................................................................................... 32 
16.1 Adverse Events (AEs) .................................................................................................... 32 
16.2 Adverse Reaction (ARs) ................................................................................................. 32 
16.3 Classification of Adverse Events and Reactions ............................................................ 32 
16.4 Notification and reporting of Adverse Events and Reactions ......................................... 33 
16.5 Notification and reporting of Serious Adverse Events .................................................... 33 
16.6 Urgent Safety Measures ................................................................................................ 33 
16.7 Annual Safety Reporting ................................................................................................ 33 
16.8 Overview of the Safety Reporting responsibilities .......................................................... 33 
17. Monitoring and auditing ......................................................................................................... 34 
18. Trial committee and investigator arrangements .................................................................... 34 
18.1 Trial steering committee (TSC) ...................................................................................... 34 
18.2 Data Safety and Monitoring Committee (DSMC) ........................................................... 34 
18.3 Investigators ................................................................................................................... 35 
19. Finance and funding .............................................................................................................. 35 
20. Indemnity ............................................................................................................................... 36 
21. Dissemination of research findings ....................................................................................... 36 
22. References ............................................................................................................................ 36 
 

                                  
 
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1. Glossary and abbreviations 
AE 
Adverse Event 
ALS 
Advanced Life Support 
APP 
Advanced Paramedic Practitioner 
CI 
Chief Investigator 
CPR 
Cardiopulmonary resuscitation 
CRF 
Case Record Form 
CTU 
Clinical Trials Unit 
CVCTU 
Cardiovascular Clinical Trials Unit 
DSMC 
Data Safety and Monitoring Committee 
ECMO 
Extra-Corporeal Membrane Oxygenation 
ECPR 
Extracorporeal Cardiopulmonary Resuscitation 
ED 
Emergency Department 
FIM 
Functional Independence Measure 
GCP 
Good Clinical Practice 
ICU 
Intensive Care Unit 
ISF 
Investigator Site File 
JRMO 
Joint Research Management Office (Barts Health/QMUL) 
LAS 
London Ambulance Service 
NHS 
National Health Service 
NIMP 
Non-investigational Medicinal Product 
OHCA 
Out-of-hospital Cardiac Arrest 
PEA 
Pulseless electrical activity 
PI 
Principal Investigator 
REC 
Research Ethics Committee 
REDCap 
Research Electronic Data Capture 
ROSC 
Return of spontaneous circulation 
SAE 
Serious adverse event 
SOP 
Standard Operating Procedure 
SPC 
Summary of Product Characteristics 
TMF 
Trial Master File 
TOR 
Terms of reference 
TSC 
Trial Steering Committee 
UK 
United Kingdom 
VA-ECMO 
Veno-arterial-ECMO 
VF 
Ventricular fibrillation 
VT 
Ventricular tachycardia 

                                  
 
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2. Signature page 
 
 
Chief Investigator Agreement 
The study as detailed within this research protocol (Version 4.0, dated 13 July 2020) will be 
conducted in accordance with the principles of Good Clinical Practice, the UK Policy Framework 
for Health and Social Care Research, and the Declaration of Helsinki and any other applicable 
regulations.  
Chief Investigator Name: 
Simon Finney 
 
Signature: 
__________________________ 
 
Date: 
____02 March 2022______ 
 
Statistician’s Agreement 
The study as detailed within this research protocol will be conducted in accordance with the current 
UK Policy Framework for Health and Social Care Research, the World Medical Association 
Declaration of Helsinki (1996), principles of ICH E6-GCP, ICH E9 - Statistical principles for Clinical 
Trials and ICH E10 - Choice of Control Groups. 
I take responsibility for ensuring the statistical work in this protocol is accurate, and I take 
responsibility for statistical analysis and oversight in this study.  
Statistician’s name: 
Thomas Godec 
Signature: 
____
________ 
 
Date: 
____02 March 2022__________ 
 
Principal Investigator’s Agreement 
The study as detailed within this research protocol (Version 4.0, dated 13 July 2020) will be 
conducted in accordance with the principles of Good Clinical Practice, the UK Policy Framework 
for Health and Social Care Research, and the Declaration of Helsinki and any other applicable 
regulations.  
Principal Investigator Name: 
Ben Singer 
 
Signature: 
__________________________ 
 
Date: 
_______02 March 2022________ 
 
 

                                  
 
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3. Summary and synopsis 
 
Short Title 
Sub30 
Methodology 
Feasibility study of a complex intervention 
Research Sites 
Barts Health NHS Trust 
London Ambulance Service NHS Trust 
Objective/Aims 
To establish whether a pre-hospital advanced physician/ paramedic 
cardiac arrest team that is ECMO capable can establish ECMO flow 
within 30 minutes of collapse 
Number of participants 
6 patients who are cannulated for ECMO 
Inclusion and 
exclusion criteria 
Male and female patients with a known or visible age of 18 to 65 
years who: 
• have a witnessed out-of-hospital cardiac arrest 
• a presumed cardiac aetiology to their cardiac arrest 
• receive bystander chest compressions within 3 minutes 
• remain in cardiac arrest at 20 minutes following collapse or fail 
to sustain ROSC in the pre-hospital setting 
The following patients will not be suitable for ECMO: 
• Identified as or visibly less than 18 years or greater than 65 
years 
• Known or visible advanced pregnancy (when resuscitative 
hysterotomy should be performed) 
• Evidence from others present at the scene or patient 
examination that ECMO unlikely to benefit patient (e.g. 
advanced frailty, advanced malignancy, …).  
• No signs of life (physical movement or breathing) AND 
evidence of ineffective chest compressions suggested by: 
- Absence of electrical activity OR 
- End tidal carbon dioxide level of less than 1.3 kPa (10 
mmHg) 
Out-of-hospital cardiac arrest encompasses both those who arrest 
prior to the emergency services being called and those who are 
witnessed to arrest by the emergency services. For the purpose of 
this study patients who suffer their first cardiac arrest whilst in transit 
to hospital will not be included. 
Statistical 
methodology and 
analysis 
Descriptive statistics will be presented summarising the process and 
outcomes of the six patients. 
Outcomes will be compared to other patients who were managed by 
London Ambulance Service on non-study days. Statistical matching 
to patients cared for concurrently with the study period will utilise a 
priori defined factors that may be associated with likely suitability for 
ECPR. Statistical matching will be individual, propensity score 
based and GenMatch guided.  
Proposed start date 
01 June 2019 
Proposed end date 
31 December 2022 
Study duration 
3 years 7 months 

                                  
 
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4. Introduction 
4.1 Out of hospital cardiac arrest – the healthcare need 
In England, 91% of patients with out-of-hospital cardiac arrest died before leaving hospital in 2015 
[1]. Within London, the London Ambulance Service (LAS) attended 10,116 out-of-hospital cardiac 
arrests (OHCA) in 2015/16 and attempted resuscitation in 4,389. Overall mortality was 91% for 
those in whom resuscitation is attempted [2]. Survival rates remain low despite improved 
bystander cardiopulmonary resuscitation (CPR), improved access to defibrillators, the introduction 
of automated compression devices and the introduction of advanced paramedic practitioners. 
Even among the subset most likely to survive (“Utstein comparator group” – bystander witnessed 
cardiac arrests with a shockable rhythm), 35.5% (199/560 in 2015/2016) of patients failed to 
achieve return of circulation and the overall mortality was 68.5% (371/542). The mortality for those 
patients with witnessed cardiac arrests but in a non-shockable rhythm was 97.5% (3,353/3,440). 
4.2 Rationale for pre-hospital ECPR 
4.2.1 
ECPR may improve outcome in refractory cardiac arrest 
Poor survival from out of hospital cardiac arrest relates to an irreversible decline in cardiac function 
and/or ischaemic injury to the rest of the body, particularly the brain. 
In 2015/16, 70% of all cases and 36% of the Utstein comparator group failed to achieve and 
sustain a return of a spontaneous circulation (ROSC) [2]. Failure to achieve sustained ROSC is a 
consequence of the precipitating pathology, insufficient coronary perfusion pressure generated by 
external chest compressions [3], significant cardiac dysfunction during transient ROSC, and the 
cardiac contusion from prolonged CPR. Failed or delayed ROSC delays treatment at the heart 
attack centre or Emergency Department (ED), and prolongs the “low blood flow” state - external 
chest compressions only generate a flow of ~0.6 L.min-1.m-2, less than one-third of normal cardiac 
output [4]. This “low flow” state perpetuates organ ischaemia multi-organ failure and hypoxic brain 
injury - the leading causes of death in the two thirds of patients who die in hospital despite 
achieving ROSC.  
Veno-arterial Extra-Corporeal Membrane Oxygenation (VA-ECMO) is a supportive technique that 
provides an effective circulation of oxygenated blood, over 2 L.min-1.m-2 – far superior to external 
cardiac massage even with mechanical devices. VA-ECMO is performed by inserting a cannula 
into a large vein to all blood to be pumped from the patient through a membrane oxygenator (that 
removes carbon dioxide and adds oxygen) and then back to the patient via another cannula 
inserted into an artery. In this way, it supports both the heart and lungs, limiting organ ischaemia 
and allowing time for the definitive treatment at the heart attack centre. Moreover, VA-ECMO 
favourably influences myocardial oxygenation by enhancing coronary perfusion through an 
increased mean arterial pressure and reduced ventricular filling pressures coupled with a 
normalisation of acid-base abnormalities and often a reduction in cardiac work. Excessive mean 
arterial pressures may increase cardiac work and are avoided. This may limit on-going cardiac 
damage and is an emerging concept (“door to unloading time”) in the management of ST elevation 
myocardial infarction complicated by cardiogenic shock [5].  
VA-ECMO is employed in a variety of clinical settings, but when used in cardiac arrest is termed 
Extracorporeal Cardio-Pulmonary Resuscitation (ECPR). The use of ECPR for in-hospital cardiac 
arrest is associated with a stepwise improvement in survival to hospital discharge depending on 
how rapidly ECPR is established: 40-50% for ECPR within 30 minutes of collapse, 30% for ECPR 
within 30-60 minutes, and 18% for ECPR beyond 60 minutes [6]. ECPR has also been used in out 
of hospital cardiac arrest, but is typically instituted in the ED. Transporting the patient to hospital 
delays ECPR, and the reported survival rates are typically lower at around 17% [7]. A recent case 
series published survival to discharge rates as high as 54% in a mix of in- and out- of hospital 
cardiac arrest patients, but the average time in survivors from collapse to ECPR was 40 minutes 
[8]. 
ECPR has never been investigated in randomised controlled trial. 

                                  
 
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4.2.2 
Pre-hospital institution of ECPR may be the best model of care 
Time to establish an adequate circulation is critical both in ECPR and conventionally managed 
cardiac arrest [6, 9-12]. The time taken to package and transport patients, after the required 
minimum of 20 minutes of advanced life support (ALS) on scene following OHCA, means that the 
earliest it is possible to institute ECPR in heart attack centres and EDs is approximately 60 minutes 
after arrest, the time at which survival starts to fall significantly. Pre-hospital ECPR instituted where 
the patient suffers a cardiac arrest may reduce this time interval. 
The technical feasibility of pre-hospital ECPR has been demonstrated [13-16]. The logistic 
challenges of delivering a complex medical intervention in the pre-hospital setting are significant. 
They include identifying and reaching appropriate patients as soon as possible after their cardiac 
arrest, establishing a sterile field, accessing femoral veins and arteries during active resuscitation 
attempts, and managing a pre-hospital scene with all the potential environmental challenges. 
The Parisian experience with pre-hospital ECPR is an excellent model to illustrate potential pitfalls. 
When pre-hospital ECPR was first introduced in Paris, the mean interval between collapse and 
ECPR was 79 minutes [15]. The ECPR team acted as a secondary response, deployed only after 
initial on-scene assessment by the primary responders, and mandatory conventional resuscitation 
for 30 minutes. Not surprisingly, these delays were associated with poor outcomes. Since then, 
they have refined their eligibility criteria and focused on faster dispatch to the scene. These 
modifications have translated into both shorter collapse-to-ECPR intervals and significantly 
improving clinical outcomes [17]. 
4.3 Current UK clinical practice for OHCA 
Most ambulance services in England follow the European Resuscitation Council guidelines for 
pre-hospital resuscitation [18], which advise at least 20 minutes of CPR for all attempted 
resuscitations. If there is failure to achieve ROSC and the cardiac rhythm is asystole, then the 
resuscitation is terminated, typically. Resuscitation may also be stopped if the cardiac rhythm is 
pulseless electrical activity (PEA) after discussion with a clinical support desk. If the rhythm is 
refractory ventricular fibrillation/tachycardia (VF/VT), the patient will be transported with on-going 
CPR to the nearest emergency department or heart attack centre. 
Hospital based ECPR is provided in a few EDs and heart attack centres throughout England on 
an ad-hoc, case-by-case basis. The UK Resuscitation Council 2015 guidelines recommend that 
ECPR should be considered as a rescue therapy for select patients in whom initial ALS techniques 
are unsuccessful [19]. There is no national protocol for its use and it has never been performed in 
a pre-hospital setting in the UK.  
4.4 Other current and planned studies of ECPR in patients suffering OHCA 
There are six other potential studies examining ECPR in patients suffering OHCA. These are 
summarised in Table 1. Indeed, a panel of experts recommended a trial of pre-hospital ECMO as 
a key study to undertake in the next 10 years [20]. 
The RECA study (Regensburg ECLS for Cardiac Arrest) aims to implement pre-hospital ECPR in 
patients between 18 and 65 years with witnessed cardiac arrests, of presumed cardiac aetiology 
(as assumed with a presenting rhythm of VF or VT) who receive bystander/healthcare worker CPR 
within 5-10 minutes. It is a single centre study run by the Universitätsklinikum Regensburg. The 
team is being dispatched via the integrated command centre in Regensburg at the same time as 
the primary response team. The study is not officially registered on any international database and 
its current status is not known. 
ACPAR2 (A Comparative study between a Pre-hospital and in hospital Circulatory support 
strategy [ECMO] in refractory cardiac ARrest; clinicaltrials.gov reference: NCT02527031) is a 
randomised controlled trial being run by the Service d’Aide Médicale Urgent (SAMU) in Paris. It 
began recruiting in March 2016. It aims to recruit 210 patients, aged between 18 and 65 years, 
who remain in medical cardiac arrest at 20 minutes. It aims to achieve VA-ECMO between 20 and 
30 minutes and compare these to patients transferred at 30 minutes to the hospital for ECPR. 

                                  
 
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Patient exclusions include those who have more than five minutes of collapse without CPR and 
those with an end tidal carbon dioxide level of less than 10 mmHg (1.3 kPa). It is powered to detect 
an increase in survival without severe neurological dysfunction from 5 to 20%.  
The CHEER3 study from the Alfred Hospital in Melbourne is being planned and aims to commence 
ECMO cannulation at 30 minutes and aiming to achieve blood flow by 45 minutes using 
percutaneous cannulation. 
EROCA (ECPR for Refractor Out-of-hospital Cardiac Arrest; clinicaltrials.gov reference: 
NCT03065647) is currently in set up and run by the University of Michigan. It aims to enrol 30 
patients over 18 months and compare conventional CPR against ECPR following expedited 
transfer to hospital with mechanical CPR for ECPR. Expedited transfer commences after the initial 
cardiac rhythm analysis and shock (if indicated). The primary outcomes are the times to arrival in 
the ED and ECPR commencing. Target times are arrival at hospital within 30 minutes and an 
additional 30 minutes to achieve ECPR.  
ECPB4OHCA (Emergency Cardiopulmonary Bypass for Cardiac Arrest; clinicaltrials.gov 
reference: NCT01605409) is a single centre study being undertaken in Vienna. The study aims to 
randomise 40 patients, aged between 18 and 75 years, to receive conventional CPR or ECPR. In 
the ECPR group expedited transfer to the hospital is imitated following 15 minutes of standard 
ALS. The primary outcome is the rate of sustain restoration of the circulation. The study 
commenced in November 2014. 
Prague OHCA study (clinicaltrials.gov reference: NCT01511666) is being undertaken by the 
Chares University, Prague. Patients, aged 18 to 65 years, suffering witnessed OHCA are 
randomised to receive in standard of care or a hyper-invasive resuscitation that includes 
mechanical chest compressions, intra-arrest nasal cooling, and early ECLS invasive assessment. 
The study aims to achieve ECMO support within 60 minutes and recruit 170 patients. The primary 
outcome is composite of survival with good neurological outcome at 6 months (Clinical 
Performance Category of 1-2). The study team is activated as soon as the Emergency Medical 
Services start to give CPR telephone advice. 
Table 1 Other studies examining ECPR in patients suffering OHCA 
Study name 
Status 
Country 
Site of 
ECPR 
Technique 
Minimum 
conventional 
CPR 
Target ECPR 
time 
RECA 
-a 
Germany 
Pre-hospital 
Percutaneous 
-a 
-a 
CAREECMO 
In set up 
France 
In hospital 
Percutaneous 
10 min 
- 
ACPAR2 
Recruiting 
France 
Pre-hospital 
Cut-down 
20 min 
<30 min 
CHEER2 
Recruiting 
Australia 
In hospital 
Percutaneous 
29 min 
Start<45 
CHEER3 
In set up 
Australia 
Pre-hospital 
Percutaneous 
30 min 
<45 min 
EROCA 
In set up 
USA 
In hospital 
Not defined 
1 shockb 
<60 min 
ECPB4OHCA 
Recruiting 
Austria 
In hospital 
Percutaneous 
15 min 
- 
Prague OHCA 
Recruiting 
Czech Rep. 
In hospital 
Percutaneous 
5 min 
<60 min 
Sub30 
In set up 
UK 
Pre-hospital 
Percutaneous 
20 min 
<30 min 
a Details not known 
b Or one rhythm analysis if a shock is not indicated 
4.5 Rationale for the Sub30 study 
The Sub30 will investigate the technical and logistical feasibility of instituting pre-hospital ECPR 
within 30 minutes of collapse for selected patients in a geographical sector of Greater London. It 
will achieve this through a unique collaboration between the primary emergency dispatch and 
response services (London Ambulance Service NHS Trust, LAS), pre-hospital practitioners (LAS 
and London Air Ambulance) and clinicians in ECMO (Barts Health NHS Trust). 
A target of thirty minutes to achieve ECMO flow is less than in published series to date. This can 
be achieved by: 
• integration into an established pre-hospital emergency response services that aggressively 
pursues ROSC through optimised ALS 

                                  
 
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• immediate deployment of an ECPR-capable cardiac arrest team as a primary resource, as 
opposed to delayed secondary deployment. Dispatch will be done by the established 
Advanced Paramedic Practitioner (APP) desk of LAS, with the objective to reach the patient 
within 8-10 minutes of the 999 call. 
• early placement of guide-wires into the femoral vessels during on-going conventional CPR, 
a procedure with low complication risk that does not commit the team to ECPR but will 
minimise the delay to ECPR support if conventional resuscitative techniques are not 
successful within 20 minutes 
• facilitated guide-wire placement through real-time wireless ultrasound delivered to the 
operator through augmented reality smart glasses 
Some OHCA are irreversible in nature and ECPR would not provide benefit to these patients. The 
ECPR team will not be task fixated on providing ECPR, but also supportive of the APP primary 
responders and provide ECPR only in settings of refractory cardiac arrest that fulfils the study 
criteria, that have been chosen based on best available evidence to identify those patients in whom 
ECPR is likely to be of benefit. 
If pre-hospital ECMO is feasible within 30 minutes of chest compressions starting, then a larger 
randomised controlled study of clinical and cost effectiveness is merited. Optimisation of the 
delivery of ECPR is vital, prior to a controlled study, in order to maximise any potential benefits for 
patients. Data from Sub30 will inform the design of such studies enabling an estimation of the size 
of any potential outcome benefits and the likely affordability for a healthcare service. Ideally studies 
would be international and multi-city to understand the generalisability of pre-hospital ECMO to 
other urban and non-urban environments. 
4.6 Risks / benefits  
The potential benefits relate to the restoration of blood flow to vital organs preventing or reducing 
neurological injury, renal failure, liver failure and cardiac failure. ECPR may also enable a patient 
to undergo coronary angiography and intervention whilst still in “cardiac arrest”. These may all 
translate to more patients surviving and survivors having better neurological outcomes. 
The potential risks to participants are: 
• vascular damage during cannulation. This will be mitigated by the use of ultrasound to guide 
the operator. 
• bleeding. This is related to the administration of anticoagulants to prevent clotting in the 
extracorporeal circuit. Anticoagulation will be monitored closely during the study. Bleeding 
is common in the context of ECMO. 
• local infection. This may be greater due to the procedure occurring outside the confines of 
a procedure room in a hospital. The risk of infection will be mitigated by using chlorhexidine 
skin preparation, allowing it to dry, large drapes to maximise the sterile field and prevent 
inadvertent contamination a single dose of prophylactic antibiotic directed against common 
skin commensal organisms. 
• individuals, who would have previously died, surviving with neurological impairment 
5. Study objectives 
The study aims to test the hypothesis that a system that overcomes the logistical and technical 
barriers to minimise the collapse-to-ECPR interval and combines an ECMO team with advanced 
pre-hospital practitioners can establish patients in refractory cardiac arrest with ECMO flow (>50% 
target) within 30 minutes of collapse. 
5.1 Primary objective 
The primary objective of the study is to assess the ability of an advanced ECMO capable 
resuscitation team to establish patients on ECPR within 30 minutes of collapse. 

                                  
 
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5.2 Secondary objectives 
The secondary objectives of the study are to assess the logistics of delivering a definitive clinical 
study of the efficacy of pre-hospital ECPR in terms of: 
• the logistics of delivering the study including potential recruitment rates 
• the safety of delivery of pre-hospital ECPR 
• the survival and neurological outcome of patients included in the feasibility study 
• the logistics of collecting data regarding resources used and the health economics 
5.3 Primary outcome 
The primary endpoint is the proportion of patients successfully established with pre-hospital ECPR 
within 30 minutes of collapse. The time of collapse will be defined as the time the call to the 
emergency services commences or the time that a patient was witnessed to suffer a cardiac arrest 
if this happens in front of the emergency services. 
5.4 Secondary outcomes 
The following secondary endpoint will be measured: 
• number of patients not dispatched to as travel time too great/team unavailable 
• number of patients in whom it is attempted to start inserting guidewires but do not meet study 
inclusion criteria at 20 minute time out. 
• the number of patients successfully cannulated between 31 and 45 minutes 
• the number of patients successfully cannulated between 46 and 60 minutes 
• proportion of patients who achieve ROSC prior to the 20 minutes timeout 
• the number of patients in refractory cardiac arrest at 20 minutes in whom ROSC is achieved 
prior to ECMO flow 
• time interval between call to the emergency services and ECPR team arrival 
• proportion of potentially supportable patients in whom guidewire placement is attempted 
• organ dysfunction during the first five days of hospital stay 
• survival to hospital discharge 
• neurological outcome at hospital discharge (Cerebral Performance Category and modified 
Rankin scales) 
• incidence of ECPR-related complications (failure to cannulate, vascular injury, site infection 
and distal leg ischaemia) 
Details about resources used and health economic data will be collected to estimate the range of 
costs and affordability of any subsequent clinical trial or clinical service. These data will include: 
• ECMO equipment used 
• duration of ECMO support 
• duration of intensive care unit stay 
• maximum organ support on the Intensive Care Unit (ICU) 
• duration of acute hospital stay 
• duration of inpatient rehabilitation following acute hospital stay 
6. Study population 
6.1 Inclusion criteria 
Male or female patients with a known or visible age of 18 to 65 years who: 
• have a witnessed out-of-hospital cardiac arrest 
• a presumed cardiac aetiology to their cardiac arrest 
• receive bystander chest compressions within 3 minutes 
• remain in cardiac arrest at 20 minutes following collapse or fail to sustain ROSC in the pre-
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Out-of-hospital cardiac arrest encompasses both those who arrest prior to the emergency services 
being called and those who are witnessed to arrest by the emergency services. For the purpose 
of this study patients who suffer their first cardiac arrest whilst in transit to hospital will not be 
included. 
6.2 Exclusion criteria 
The following patients will not be suitable for entry into the study: 
• Known to be are visibly appear younger than 18 years old or older than 65 years. 
• Known or visible advanced pregnancy (when resuscitative hysterotomy should be 
performed) 
• No signs of life (physical movement or breathing) AND evidence of ineffective chest 
compressions suggested by: 
- 
absence of electrical activity at 20 minutes time out OR 
- 
end tidal carbon dioxide level of less than 1.3 kPa (10 mmHg) 
• Evidence from others present at the scene or patient examination that ECMO unlikely to 
benefit patient (e.g. advanced malignancy, severe frailty). The narrative of this decision will 
be recorded in the Case Record Form (CRF). 
7. Study design 
7.1 Overall design 
The study is a  feasibility study of a complex intervention performed on two study sites. 
7.2 Setting and timescale 
The study will be undertaken in North East London over approximately 12 months. The study site 
is Barts Health NHS Trust. 
7.3 Timescale 
The study will only be performed on study days when the ECMO team is available. It is anticipated 
that this will be 2-3 days per week. It is anticipated that it will take up to 52 study days to recruit 
six patients. 
7.4 Patient identification / ECPR Team activation 
On study days, the ECPR team will be active in a fast response blue light emergency response 
car provided by London’s Air Ambulance. They will have no other clinical or non-clinical duties. 
On study days, the team will assemble at the Royal London Hospital and perform 
challenge/response checks on their equipment and vehicle. Once complete they will inform control 
that they are active and available. At various points in the day the team will be based in 
geographical areas where London Ambulance Service have attended the most cardiac arrests 
historically. At the end of the shift the team will inform control that they are standing down. 
The team will be activated by the Advanced Paramedic Practitioner (APP) desk in the Emergency 
Operations Centre at London Ambulance Service. This desk screens in real time all calls to the 
emergency services that may be a cardiac arrest and dispatch additional APPs to the scene. They 
listen in on all calls where it is indicated on the pre-triage questions, asked by the call handler, that 
the patient is not breathing or has abnormal breathing. In addition, they screen calls as requested 
by the dispatchers. Their clinical experience at listening to calls will enable the LAS sit to identify 
trial subjects and dispatch the ECPR team as an additional emergency response within 2-3 
minutes of the emergency call being placed. They will task the ECPR team if the estimated time 
of travel to the scene is 20 minutes or less. 
All ‘patients’ for whom the team is activated will be included in the screening log. In addition to 
patients who are enrolled and receive ECMO, the log will indicate those people who were never 
assessed (as the team was stood down prior to arrival), those whose were assessed but clearly 

                                  
 
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did not meet inclusion/exclusion criteria (Section 8.2) and those in whom guidewires were inserted 
but were not formally enrolled in the study at the 20 minute time out (Section 8.5) 
7.5 Consent waiver at enrolment 
Patients are unable to provide consent to enter the study at the point of enrolment as they lack 
capacity since they are unconscious and in cardiac arrest. This situation is sudden and unexpected 
preventing prior consultation with the patient and prospective consent. Their capacity will not vary 
throughout the intervention period as they will remain in cardiac arrest and unconscious. Since 
there are no alternative groups of patients in whom this study could be conducted it is necessary 
to recruit patients who lack capacity. 
It is unlikely that if it were possible to consult a personal consultee, in the context of the distress 
of learning the patient is in cardiac arrest, that any such person could be able to make an informed 
decision in the limited time available. 
Since delays in resuscitation and emergency treatments are associated with worse patient 
outcomes, it is not practical in this study to consult a professional consultee, such as their general 
practitioner, without placing the participant at potential harm from delayed treatment.  
Therefore, patients will be enrolled without specific consent at the start of the study if they meet 
eligibility criteria. This was specifically discussed at a patient and public engagement event 
(Section 12) and was considered universally acceptable by the attendees. 
If a patient is wearing a MedicAlert bracelet that indicates they have indicated an Advance 
Decision about their care, and there is sufficient time to find out about the Advance Decision then 
this will be undertaken and respected if the Decision is considered to be valid and within the 
context of the clinical scenario. An indication by a patient that they would not wish to receive blood 
products will not preclude them receiving ECPR. Any Advance Decisions will be discussed with 
the Barts Health NHS Trust legal time at the earliest opportunity. 
7.6 Consent to on-going inclusion in the study 
ECMO support will be life-sustaining. A personal consultee will not be asked if the participant 
should remain in the study. Nevertheless, they will be consulted about the patient’s other medical 
conditions and likely wishes and these will be considered, according to standard clinical practice, 
by the attending physicians who will not be study investigators. Family and friends of study 
participants will be given information about the study as soon as is practicable. 
Participants will be approached if they regain capacity to inform them of their participation in the 
study. This will be done prior to hospital discharge and usually on the hospital ward when they are 
no longer critically unwell. Individual patients can ask to be withdrawn from the study if they request 
to do so. Data already collected will be processed. The legal basis for processing these data, 
which include special category data, is as a task in the public interest as outlined in General Data 
Protection Regulation and the Data Protection Act (2018). Patients will not be required to provide 
a reason for wanting to withdraw from the study. Withdrawal will not influence the goals of on-
going medical care for a patient.  
7.7 Provision of public information about the study 
We will disseminate information about the study through LAS, Barts Health, and London Air 
Ambulance. Media used for information will include the internet, newsletters, posters, annual 
reports and discussion at public meetings. The public will be directed to the trial website for further 
information. 
People will be able to decline participation in the trial in the event they sustain a cardiac arrest. 
Requests not to participate will be sent to the Chief Investigator who will ensure a that a stainless 
steel “No Sub30 study” bracelet is issued to the person’s home address.  

                                  
 
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7.8 Co-enrolment in other clinical studies 
Patients in Sub30 are eligible for co-enrolment in other studies and the scientific validity of this will 
be decided by the Chief Investigator on a case by case basis in keeping with the UK guidelines 
for critical care research [21]. Co-enrolment with any studies should be documented in the CRF. 
7.9 End of study 
The end of the study is defined as 90 days after the final patient is recruited into the study. 
The study will be discontinued early if the sponsor or Data Safety and Monitoring Committee 
request the study to be stopped. The Trial Steering Committee will advise how to manage patients 
receiving ECMO as study participants when this decision is made. 

                                  
 
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7.10 Study Scheme Diagram 
 
8. Study procedures 
The delivery of pre-hospital ECMO is a complex procedure that encompasses dispatch of the 
ECPR team to the patient, assessment, institution of ECMO, transfer to Heart Attack Centre and 
then on-going care at the Heart Attack Centre in the cardiac catheterisation laboratory, intensive 
care unit and ward. Full details are provided in the latest approved version of the Study Manual. 
This section contains a synopsis of the key aspects of care. 

                                  
 
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8.1 ECPR Team members 
The ECPR team will comprise of: 
• A pre-hospital emergency medicine consultant 
• An advanced paramedic practitioner/Helicopter emergency medical paramedic 
• Two ECMO consultant as defined in the St Bartholomew’s Hospital Local Policy for 
Accreditation of medical and nursing staff as ECMO specialists (SBH-POL-01-2016-012 or 
any superseding version) 
Only the ECMO consultants will perform the ECMO intervention on the study subjects (Sections 
8.6 and 8.7), and the other members of the ECPR team as detailed in Section 8.3 are available 
for medical support, but will act as observers in relation to ECMO management. 
8.2 Primary assessment 
All team members will follow the current Barts Health NHS Trust and London Ambulance Service 
NHS Trust procedures regarding protection of patients and staff from SARS-CoV-2 infection. On 
arrival at the scene the ECPR team will assess whether the inclusion criteria or exclusion criteria 
are met. They will also undertake a comprehensive bilateral assessment of the pupillary response 
to light using an automated pupillometer (NPI-200, NeurOptics, Irvine, California). 
If the inclusion and exclusion criteria are definitely not met they will: 
• Assist alternative LAS resources present on scene as required. Once assistance is no longer 
required the ECPR team will stand down and inform control that they are available for further 
tasking to cardiac arrests. 
• Provide the primary response, if there are no LAS resources on site, irrespective if the patient 
is in cardiac arrest or not. They will use standard LAS treatment protocols. Upon arrival of 
alternative LAS resource then the ECPR team will hand over care of the patient to that 
resource and stand down unless on-going assistance is required by LAS. On standing down 
the ECPR team will indicate to control that they are available for further tasking to cardiac 
arrests. 
If inclusion criteria are met and no immediate exclusion criteria identified, then ECPR pre-hospital 
team members (Pre-hospital medicine consultant and paramedic) will split from the two ECMO 
consultants who will concurrently fulfil their roles and responsibilities.  
8.3 ECPR Pre-hospital team roles and responsibilities 
The pre-hospital ECPR team will endeavour to achieve ROSC by delivering and supporting others 
in delivery of ALS to the patient. They will: 
• introduce the ECPR team to any on scene healthcare resources 
• manage the cardiac arrest following London Ambulance Service and Resuscitation Council 
ALS Guidelines 
• seek ROSC by addressing reversible causes, ensuring advanced airway management and 
optimising resuscitation including automated mechanical compressions 
• administer intravenous fluids to aid percutaneous cannulation by the ECMO team as 
required 
• manage the pre-hospital environment and ensure team safety 
• establish 360 degrees access to the patient 
• establish collateral history about the patient, the collapse, and the timings of resuscitation 
attempts 
• prepare for team timeout if cardiac arrest is refractory at 20 minutes of resuscitation by 
healthcare professionals 
8.4 ECMO consultants’ initial roles and responsibilities 
The ECMO consultants will establish a sterile surgical area in the patient’s groin and using real-
time ultrasound guidance to percutaneously insert guide wires into the patient’s femoral artery and 
vein. The position of wires in the aorta and inferior vena cava respectively will be confirmed using 

                                  
 
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subcostal/trans-hepatic ultrasound. They will also complete the priming of the CardioHelp circuit 
so it is ready for use. If chest compressions must be interrupted for insertion of the 
needle/guidewire then this will be for no more than ten seconds (as timed by the consultant in pre-
hospital medicine) and attempts made to coordinate these with any pulse checks. 
If ROSC is achieved prior to 20 minutes of resuscitation then any wires present at that point will 
be used to insert 6Fr angiography sheaths into the femoral artery and/or vein to facilitate care at 
the Heart Attack Centre. The team will then continue to support LAS as required to provide 
standard post-resuscitation care and expedited transfer to the nearest Heart Attack Centre. 
8.5 Twenty minute time-out if patients remains in cardiac arrest 
Twenty minutes after the start of resuscitation by a healthcare provider a team time out will be 
called. Cardiopulmonary resuscitation will continue during this time out. 
The pre-hospital consultant will present the patient using the Situation Background Assessment 
Recommendation (SBAR) format. The assessment will include reciting the inclusion and exclusion 
criteria in a challenge response manner. If the team considers that there are no exclusion criteria 
met then the ECMO consultants will proceed to cannulate the patient’s femoral artery and vein 
and commence ECMO support. In the interval between 20 minutes of resuscitation and ECMO 
support, no more epinephrine (adrenaline) boluses will be administered. If chest compressions 
must be interrupted for insertion of the cannulae then this will be for no more than ten seconds (as 
timed by the consultant in pre-hospital medicine). 
If an exclusion criterion is identified then any wires present at that point will be used to insert 6 Fr 
angiography sheaths into the femoral artery and/or vein which may facilitate on-going care. The 
team will then continue to support LAS as required. All patients will be followed up for adverse 
events related to the insertion of guidewires for seven days following the cardiac arrest. No other 
data, other than that included in the screening log, will be collected for these patients. 
If cannulation cannot be achieved within 60 minutes then further attempts will not be continued 
and the patient reviewed and consideration made to declare life extinct or transport the patient 
under ongoing CPR to the nearest emergency department. 
8.6 ECMO support 
Target parameters for initial ECMO support and the on-going care of the patient on ECMO are 
outlined in the ECMO Study Manual. ECMO support will endeavour to ensure perfusion of the vital 
organs whilst minimising any reperfusion injury and be based on any clinical and preclinical data 
available. 
8.7 Transfer to the Heart Attack Centre at St Bartholomew’s Hospital 
Patients will be transferred to the Heart Attack Centre at St Bartholomew’s Hospital by the two 
ECMO consultants and London Ambulance Service. The Heart Attack Centre will be pre-alerted 
using the current systems in process that alert the teams as to whether patients are “self-
ventilating” or “ventilated”. An additional category of “ECMO supported” will be included. 
8.8 Post-resuscitation care 
Following arrival at the Heart Attack Centre the care of the patient will be managed by standard 
algorithms outlined in the Study manual. These will essentially follow the Standard Operating 
Procedures and Policies of St Bartholomew’s hospital. These consider: 
• assessment of the need for coronary angiography 
• complete versus culprit-only revascularisation 
• use of intra-aortic balloon counter-pulsation 
• use of therapeutic hypothermia 
• haemodynamic management on ECMO 
• management of distal leg perfusion 
• anticoagulation management 
• weaning from VA-ECMO 

                                  
 
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• general intensive care unit care 
• neurological assessment 
8.9 Schedule of assessments 
The time of ECMO blood flow >50% target will be recorded on the CRF. 
Many assessments will be made as part of routine clinical practice. These will include computed 
tomography of the brain, electroencephalograms, somatosensory evoked potentials, markers of 
kidney, liver, heart and lung function. If these are done, then the results will be recorded in the 
CRF. They are outlined in Table 2. 
In addition, other a variety of physiological, biomarkers, and functional outcome measures, that 
are not part of routine clinical practice, will be recorded as secondary outcomes for the study as 
outlined in Table 3. 
Table 2 Standard clinical assessments made that will be included in CRF (if undertaken by clinical team) 
Assessment 
4 h 
24 h 
Any time point in 7 d 
RIFLE scorea 
 
✓ 
 
Computed tomography of brain 
 
 
✓ 
Electroencephalography 
 
 
✓ 
Somatosensory evoked potentials 
 
 
✓ 
Liver function testsb 
✓ 
✓ 
✓ 
Echocardiographyc 
 
 
✓ 
Vital signsd 
✓ 
✓ 
 
Vasoactive medication usee 
✓ 
✓ 
 
Coagulation assessmentsf 
✓ 
✓ 
 
a  The RIFLE score is a classification of acute kidney injury based on creatinine levels and urine output 
b  Specifically bilirubin, aspartate transaminase, alkaline phosphatase 
c  A comprehensive study as outlined by the British Society of Echocardiography 
d  Including heart rate, blood pressure, right atrial pressure, pulmonary artery occlusion pressure, cardiac output and 
arterial lactate 
e  Including adrenaline, noradrenaline, dobutamine, dopamine, milrinone, enoximone, levosimendan 
f  Including prothrombin time, activated partial thromboplastin time, fibrinogen, platelet count 
Table 3 Non-routine assessments made during the study 
Assessment 
Pre-ECMO 
Time of hospital admission 
Hospital 
90 
0 h 
24 h 
48 h 
72 h 
discharge 
days 
Bilateral pupillometry 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
Serum Neuron Specific Enolase 
 
✓ 
✓ 
✓ 
✓ 
 
 
Plasma/Serum biobanked 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
Modified Rankin Scale 
 
 
 
 
 
✓ 
✓ 
Function Independence Measure 
 
 
 
 
 
✓ 
✓ 
EQ-5D 
 
 
 
 
 
 
✓ 
 
8.10 Standard Operating Procedures 
The most current standard operating procedures of the Cardiovascular Clinical Trials Unit will be 
adopted for the conduct of this study. Specific operating procedures have been formulated for 
other trial activities are outlined in Table 4. 
Table 4 Trial specific Standard Operating Procedures 
Name 
Version 
Date 
Using the Functional Independence Measure (FIM) 
1.0 
20 Aug 2018 
Maintaining chain of custody for trial disposables and medical gases 
1.0 
20 Aug 2018 
Maintaining chain of custody for trial samples 
1.0 
20 Aug 2018 
Assessing patients with the modified Rankin Scale 
1.0 
20 Aug 2018 
Assessing patients with the EQ-5D-5L instrument 
1.0 
20 Aug 2018 

                                  
 
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Completion of Case Report Forms 
1.0 
20 Aug 2018 
Environmental monitoring of storage areas 
1.0 
25 Mar 2019 
Media and publicity 
1.0 
01 Mar 2019 
9. Assessment and management of risk 
The details of the risk assessment regarding the study and the mitigating factors put in place are 
outlined in Table 5. 

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Table 5 Risk assessment and mitigation for Sub30 study 
Risk details 
Initial Assessment* 
 
Mitigating actions 
Reassessment 
PSR 
PLR 
RRN 
PSR 
PLR 
RRN 
Vascular damage during cannulation 
Large cannula (typically 17-25 Fr) are being inserted into the 
femoral artery and vein. This may be associated with damage 
to the vessel and extensive bleeding. Cannulation is likely to 
be more difficult out of the ICU/operating room due to patient 
position, weather, and unfamiliar environment 
3 
3 
9 
Use of experienced Consultant operators 
utilising ultrasound for vascular cannulation. 
3 
2 
6 
Infection – Local 
Pre-hospital ECMO is occurring outside a normal operating 
environment and there is greater risk of environmental 
contamination of the cannulation site and infection in the 
patient. 
3 
3 
9 
Chlorhexidine preparation of skin. Careful 
cleaning of cannulation sites on return to 
hospital environment. Use of prophylactic 
antibiotics. Aseptic technique. 
Consideration made for need to re-cannulate at 
an alternative sterile site on return to Barts 
Heart Hospital if the access sites were heavily 
contaminated. 
3 
2 
6 
Neurological injury established pre-ECMO 
Neurological injury may be sustained during the period of 
cardiac arrest despite bystander CPR. 
4 
4 
16 
Use of mechanical compression device to 
maximise efficacy of chest compressions whilst 
ECMO instituted. 
Minimisation of secondary brain injury with 
avoidance of hyperthermia, consideration of 
cerebral perfusion pressure, good glycaemic 
control. 
In the setting of continued low blood flow 
further primary brain injury will be minimised by 
more aggressive cooling. 
Pre-hospital ECMO is proposed as method of 
risk reduction for neurological injury in patients 
who survive. 
3 
3 
9 
Bystander interference during cannulation 
Cannulation will be done surrounded by members of the 
public and emergency services. Wishing to help they may 
disrupt the functioning of the cannulation team preventing 
their effective operation. 
3 
3 
9 
Tasking of emergency services to control the 
environment and bystanders. Utilisation of 
consultants in pre-hospital care for scene 
management. 
 
2 
1 
2 
Adverse climate 
Wind, cold, and rain may make the cannulation difficult. 
2 
3 
6 
Use of IPX4 standard equipment if possible to 
counter effects of rain. Covers utilised for other 
equipment. 
Weights for drapes to counter wind 
Suspension of service if conditions considered 
too adverse to safely deliver pre-hospital 
ECMO 
2 
2 
4 

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Adverse publicity for Trust/Organisations involved 
An adverse outcome for the patient (severe neurological 
injury but survival; or death despite significant and prolonged 
intervention) may be perceived in retrospect as an 
inappropriate use of healthcare resource (e.g. ICU capacity, 
blood products). 
2 
3 
6 
Discussion with Communications team prior to 
the event – avoid all public comments until 
patient outcome known and consent of patient 
gained. 
Aim to undertake resuscitation out of public 
view  
2 
2 
4 
Reduced capacity to support other patients 
Any patient will take up ICU capacity in terms of bed spaces, 
staffing, and equipment. This may limit the ability to support 
the work of elective cardiac surgery or emergency respiratory 
ECMO. 
2 
3 
6 
Pre-hospital ECMO team are additional to the 
standard ECMO team which would not be 
influenced by the activity. 
Planning with the theatre schedulers and 
cardiac surgeons regarding. 
2 
2 
4 
Failure to cannulate femoral vessels 
Expected failure rate of 5-10% of percutaneous cannulation 
of femoral vessels in cardiac arrest.  Failure would negate 
ability to initiate ECPR. 
3 
4 
12 
Experienced consultants, cannulating with the 
use of ultrasound, Saline fluid infusion to 
improve vessel size. 
Augmented reality ultrasound glasses to 
improve technique. 
Any failure to cannulate would mean patient 
would receive standard ongoing care as per 
LAS resuscitation protocols. 
2 
4 
8 
Leg ischaemia – arterial 
The size of the arterial cannula can impair blood flow to the 
ipsilateral limb. A distal limb perfusion cannula will be difficult 
to insert in the pre-hospital environment 
3 
4 
12 
Routine insertion of a distal limb perfusing 
catheter on return to the Barts Health. 
Use of smaller arterial cannulae (15Fr). 
3 
2 
6 
Infection of patients with SARS-CoV-2 
There is a risk of healthcare workers infecting the patient. This 
may occur acutely in the resuscitation and subsequent 
hospital care but also when the patients are followed up at 90 
days. 
4 
2 
8 
Research team will wear full respiratory PPE 
during their attendance at the cardiac arrest 
and their continuing care until they leave the 
patient area. 
Staff at St Bartholomew’s hospital wear 
appropriate PPE for the patient’s risk status 
and never wear less than gloves and surgical 
face mask for any patient. 
Research team will be screened for infection 
(symptoms and temperature) at the start of 
each shift. 
Use of video-consultation in follow up (a 
practice that has been adopted in our critical 
care service) 
4 
1 
4 

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Infection of Research Staff with SARS-CoV2 
There is a risk of the patient infecting research staff with 
SARS-CoV-2. Patients with OHCA are more likely to have 
SARS-CoV-2. 
3 
2 
6 
Cleaning and decontamination of LAA fast-
response vehicle as part of morning checks 
Surgical masks to be worn by all team 
members while in car (except navigator when 
giving driver instructions on blue lights) 
Team no longer roaming but based in a (pre-
agreed) LAS ambulance station observing all 
local COVID-19 precautions at said station 
Formal ‘doffing’ and decontamination before 
every patient contact, presuming all patients 
are a COVID-19 infection risk 
Consideration 
of 
not 
bringing 
ECMO 
equipment and any non-essential equipment 
into ‘Hot zone’ near patient until confirmed 
potential Sub30 patient (Team-leader role to be 
updated) 
Additional sealed PPE grab-bag added to 
equipment and relevant checklists 
Symptom and temperature check all team 
members at start of study day 
If symptoms of COVID-19 develop during a 
shift then the study day will be cancelled and 
the team will self-isolate according to current 
Barts Health NHS Trust guidance. 
All patients screened for SARS-CoV-2 infection 
on arrival to hospital, according to Barts Health 
NHS Trust standard practice. 
All patients considered to be potentially 
infected SARS-CoV-3 – so are managed with 
full aerosol protecting PPE until  infectio 
3 
1 
3 
Negative impact on staff wellbeing with participation 
The additional workload or personal risk factors may mean 
some of the study team no longer wish to participate in the 
study. 
Staff are uncomfortable wearing PPE for long periods of time. 
3 
3 
9 
Reinforce that all shifts are voluntary and there 
is no obligation for trained pool to continue in 
the study. 
Individual Barts Health NHS Trust COVID-19 
risk assessment made prior to any team 
member joining the study 
Additional section to shift de-brief form specific 
to 
any 
COVID-19 
related 
concerns 
or 
suggestions  
2 
2 
4 
* PSR – Potential Severity Rating; PLR – Potential Likelihood Rating; RRN – Risk Rating Number (PSR x PLR) 

                                  
 
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10. Statistical considerations 
10.1 Sample size 
This is a single group study. No power calculation has been undertaken. The estimated sample 
six patients in whom cannulation is attempted following the twenty minute time out (see Section 
8.5) was selected to allow robust data to support a future efficacy study. 
10.2 Methods of Analysis 
Data will be analysed using a combination of Excel for Mac 2016 (Microsoft Corporation), Prism 5 
(GraphPad software) and R. Summary data will be presented as a median and range for all six 
patients. Categorical data will be presented as raw data. 
Patient mortality will be compared to other patients who were managed by LAS on non-study days. 
These data are stored in a bespoke Cardiac Arrest database, for which London Ambulance 
Service NHS Trust is the Data Controller. Only patients cared for concurrently with this study will 
be used for matching. London Ambulance Service NHS Trust will provide these data to the Chief 
Investigator after the last patient has been enrolled. 
Patients will be matched based on their likelihood of receiving ECMO on a one to many basis. 
Potential matches will be first screened for the study inclusion and exclusion criteria. A priori 
defined factors that may be used to estimate this likelihood of receiving are: 
• age (closest match to 5 years) 
• time of first LAS resource attendance on scene (closest match to 5 minutes) 
• presumption of a cardiac aetiology to the arrest 
Three techniques will be used in matching – individual matching, propensity score matching and 
GenMatch matching. Matching will be undertaken with replacement. Missing data will not be 
imputed. 
11. Ethical and regulatory considerations 
11.1 Protocol 
This protocol was constructed in line with the SPIRIT 2013 recommendations [22]. Approval of the 
protocol was granted by the Trial Steering Committee. 
11.2 Peer review 
Independent expert peer reviews of this protocol were sought from: 
• The Barts Heart Centre Peer Review Committee 
• The international ECMO Network (ECMONet) 
11.3 Management of actual and potential conflicts of interest 
The guidelines of the International Committee of Medical Journal Editors will be used for 
disclosures of any conflicts of interest (financial and non-financial). Each investigator and member 
of TSC or DSMC must disclose any conflicts of interest prior to commencing the study. These data 
will be included in the Trial Master File and be renewed every six months. Any reported conflict 
will be discussed with the Sponsor and Funders. 
11.4 Summary of main ethical, legal and management issues 
The main ethical considerations are:  
• Emergency enrolment of patients who lack the capacity to provide consent 
Patients are unable to provide consent to enter the study at the point of enrolment as they 
lack capacity since they are unconscious and in cardiac arrest. This situation is sudden and 
unexpected preventing prior consultation with the patient and prospective consent. Their 
capacity will not vary throughout the intervention period as they will remain in cardiac arrest 

                                  
 
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and unconscious. Since there are no alternative groups of patients in whom this study could 
be conducted it is necessary to recruit patients who lack capacity. 
If it were possible to find a personal consultee for the patient, it is unlikely that the consultee 
could make an informed decision about the study in the limited time available and in the 
context of the distress of learning the patient is in cardiac arrest. 
Since even short delays in resuscitation and emergency treatments are associated with 
worse patient outcomes, there is insufficient time to find and contact a professional consultee 
such as the patient’s general practitioner. 
Finally, it is considered that since the intervention is likely to benefit the patient directly and 
that this is proportional to the burden of taking part; particularly in the context that they are 
in cardiac arrest and have a rate of survival of less than 10% without any additional 
intervention. 
If established, ECMO support will be life-sustaining. Therefore a personal consultee will not 
be asked if the participant should remain in the study. Nevertheless, they will be consulted 
about the patient’s other medical conditions and likely wishes and these will be considered, 
according to standard clinical practice, by the attending physicians who will not be study 
investigators. Family and friends of study participants will be given information about the 
study as soon as is practicable in the form of face to face discussions and information 
leaflets. 
Participants will be approached if they regain capacity to inform them of their participation in 
the study. This will be done prior to hospital discharge and usually be on the hospital ward 
when they are no longer critically unwell. Individual patients can ask to be withdrawn from 
the study if they request to do so. The patient will not be required to provide a reason for 
wanting to withdraw from the study. Withdrawal from the study will not influence the goals of 
on-going medical care for that patient. 
If patients never regain capacity due to death or severe neurological injury then they will 
never be an opportunity to ask them about their inclusion in the study. We will retain and 
process any data collected about the patient within the constraints outlined the General Data 
Protection Regulation. We will retain some of the excess plasma and serum collected as 
part of routine clinical measurements during the clinical care of the patient. 
• Are the results generalisable to other geographical areas? 
This feasibility trial involves a collaboration between Barts Health, London Ambulance 
Service and London’s Air Ambulance. These are three well-resourced institutions who have 
established the logistics to deliver very rapid emergency pre-hospital care in London. If the 
study demonstrates it is feasible to deliver ECPR within 30 minutes in London, is this 
generalisable to other urban and non-urban areas? 
A key aspect of this study design is testing the training and simulation that has developed 
the new ECMO team and these will translate to other geographic areas. It is very likely that 
other urban centres will be able to replicate the service. We have been approached by other 
centres keen to participate in a multicentre outcome study if feasibility is demonstrated. 
By contrast, it may take longer for an ECMO team to attend patients in non-urban settings 
due to the distances that need to be covered but in part mitigated by reduced traffic. Whilst 
a 30 minute threshold may not be possible in these settings although the processes and 
lessons learnt may enable accelerated ECPR in these settings too. This parallels the 
different provision in rural areas for other service such as major trauma centre access or 
emergency primary coronary intervention access. 
• ECPR may increase survival but with neurological injury 
If ECPR restores blood flow to the patients’ vital organs such as the heart, liver, brain, 
kidneys and gut it is possible that this is sufficient to enable the patient to survive but 
insufficient to prevent brain injury. However, observational data from patients who receive 

                                  
 
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ECPR suggest that the proportion of surviving patients without severe neurological injury 
improves. Nevertheless this question will be a core question of any outcome study if the 
current study demonstrates the feasibility of the intervention. 
• Maintenance of patient dignity and privacy in the pre-hospital setting 
We specifically asked at a public engagement event about patient dignity and the impact of 
a procedure which required insertion of plastic tubes into the groin and exposure of the 
patient’s lower abdomen, pelvis and upper thighs. The universal opinion was that this was 
unavoidable and outweighed by the potential benefits of the intervention. We will endeavour 
to maintain patient dignity by utilising windowed drapes that will cover a patient again apart 
from a small region in the upper thigh. Moreover, the paramedics and pre-hospital physicians 
in this study are well versed in scene control and will manage bystanders appropriately. They 
are often assisted in this by the simultaneous attendance of the police in public areas. 
• ECPR may impede standard ALS algorithms 
Institution of ECPR could impede standard ALS algorithms as pipes are inserted into the 
femoral vessels. Our protocol does not involve any interruption of conventional resuscitation 
which will continue for at least 20 minutes – the time period when a return of spontaneous 
circulation (ROSC) is most likely and a scenario that is best for the patient. Following 20 
minutes the number of patients who go on to survive without disability are few and 
proportionally reducing rapidly. By contrast the number of patients who go on to die or who 
have severe disability are many and increasing rapidly. This justifies the addition of an 
alternative resuscitation strategy to augment the continued standard resuscitation 
algorithms. Most ambulance services in England follow the European Resuscitation Council 
guidelines for pre-hospital resuscitation, which advise at least 20 minutes of CPR for all 
attempted resuscitations. If there is failure to achieve ROSC and the cardiac rhythm is 
asystole, then the resuscitation is terminated typically. Resuscitation may also be stopped if 
the cardiac rhythm is pulseless electrical activity (PEA) after discussion with a clinical 
support desk. If the rhythm is refractory ventricular fibrillation/tachycardia, the patient will be 
transported with on-going CPR to the nearest emergency department or heart attack centre. 
• Pre-hospital ECPR may be associated with a higher risk of procedural complications 
Undertaking a complex in-hospital procedure in the pre-hospital environment could 
potentially increase the risk of complications from the procedure. We have completed a 
complex risk assessment matrix within our protocol and have introduced measures to reduce 
all risks. In published reports of pre-hospital ECPR, the complication rates are no more than 
that of in-hospital ECPR.  
An alternative strategy to institute ECPR earlier is to start moving the patient the hospital to 
earlier (colloquially called to 'scoop and run').  Since it is not possible to prospectively identify 
patients who cannot be resuscitated within 20 minutes, this strategy will require all patients 
to be transport immediately to hospital with chest compression continuing en route. Evidence 
has demonstrated that CPR is inferior during transport and therefore such a strategy would 
risk potential early ROSC in patients by delivering sub-optimal resuscitation in a bid to 
shorten transfer times. 
11.5 Research Ethics Committee (REC) review and reports 
The Chief Investigator (CI) has obtained approval for this study from the London Harrow NHS 
Research Ethics Committee. The study will be submitted for Site Specific Assessment at St 
Bartholomew’s Hospital. The Chief Investigator will require a copy of the Site Specific Assessment 
approval letter before the study can commence.  
All substantial amendments that require review by the REC will not be implemented until the REC 
and Sponsor grant a favourable opinion regarding the amendment. 
All correspondence with the REC will be retained in the Trial Master File. It is the Chief 
Investigator’s responsibility to provide an annual progress report will be submitted to the REC 
within 30 days of the anniversary date on which the favourable will was given, and annually until 

                                  
 
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the trial is declared ended (Section 7.9) The CI will notify the REC when the trial ends, even if this 
is early. In the context of early discontinuation, the REC should be informed of the reasons for 
this. The CI will be responsible for submitting a final report within one year of the end of the study, 
indicating the results and any publications or abstracts to date. 
11.6 Annual Safety Reporting  
The CI will send an Annual Progress Report to the REC and the sponsor using the Health 
Research Agency template on the anniversary of the REC “favourable opinion”. 
12. Public Involvement 
Patients and publics were involved in the design of this study through a Patient and Public 
Engagement event held at 2 May 2017. Specific questions asked in addition to a general open 
session centred around: 
• concerns about consent and permission to enter a study when patient lacks capacity since 
they are in cardiac arrest 
• concerns about preserving patients’ dignity, autonomy, and privacy in the context of 
resuscitation that is happening outside a healthcare setting 
• appropriate outcome measures that may demonstrate benefit or harm 
• communication of the study to a wider audience 
A lay person will be asked to join the Trial Steering Committee and will contribute to the 
discussions on the study management and dissemination of findings. 
The study will be registered with the INVOLVE open-access database which registers healthcare 
projects 
involving 
members 
of 
the 
public 
as 
partners 
in 
the 
research 
process 
(http://www.invo.org.uk).  
13. Data handling and record keeping 
13.1 Data management 
Study data will be collected and managed using REDCap electronic data capture tools hosted at 
Queen Mary University of London. REDCap (Research Electronic Data Capture) is a secure, web-
based application designed to support data capture for research studies, providing 1) an intuitive 
interface for validated data entry; 2) audit trails for tracking data manipulation and export 
procedures; 3) automated export procedures for seamless data downloads to common statistical 
packages; and 4) procedures for importing data from external sources.  
Each major version of the CRF must be authorised by the Trial Steering Committee. Minor 
versions correcting typographical errors can be authorised by the Chief Investigator. All versions 
will be stored in the Trial Master File.  
Each patient will be identified by a unique participant identification code. All person identifiable 
data will be logged on the Study Identification Log which will be part of the Investigator Site File, 
and used by the study team for participant contact. A study enrolment log will be maintained with 
pseudo-anonymised participant data.  
Signed completed CRFs will be stored along with copies of source data (e.g. ambulance run sheet, 
medical records, clinical charts, drug charts) in the Investigator Site File which will be maintained 
in a secure location at St Bartholomew’s Hospital. The CRF will be compliant with the CVCTU’s 
Standard Operating Procedure for Trial Data Management. The Trial Master File (TMF) will be 
maintained by the CVCTU and kept in a secure, restricted access office within the William Harvey 
Research Institute. 
13.2 Source data 
All versions of Consent Forms must be the authorised by the Sponsor and REC. All versions will 
be stored in the Trial Master File. 

                                  
 
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All original signed consent forms will be stored in the Investigator Site File. Copies will be scanned 
and inserted in the Cerner Millennium Electronic Health Record of Patients. The consenting 
procedure will follow the CVCTU’s Standard Operating Procedure and the investigator taking 
consent will be trained in consent procedures and Good Clinical Practice (GCP).  
If possible, source data will be collected directly into the REDCap. In the pre-hospital setting this 
will not be possible and data will be collected onto a paper CRF which will be transferred to the 
REDCap subsequently. A source data agreement will be written to specify where the source will 
be located. All source data will be kept securely in the participant study files within locked cabinets 
in restricted access rooms in St Bartholomew’s Hospital.   
All times will be recorded in Coordinated Universal time (UTC) to avoid confusion over transitions 
between British Summer Time and GMT. All times (e.g. medical devices, LAS dispatch desk, 
research clocks in study equipment, watches) will be assessed for accuracy against the time.is 
time server. 
13.3 Confidentiality 
The investigators will preserve the confidentiality of participants taking part in the study in line with 
General Data Protection and Regulation and Data Protection Act (2018), NHS Caldicott principles, 
and UK Policy Framework for Health and Social Care. Data access will be granted to authorised 
representatives from the Sponsor, St Bartholomew’s Hospital and any regulatory authority to 
permit monitoring, audits and inspections. 
All paper files will be stored in locked cabinets in restricted access rooms. 
Any electronic records of the data created during analysis of the study will not contain person 
identifiable data and will be stored on a network drive of Barts Health NHS Trust. Access to this 
area will be granted to the named study investigators. 
The LAS provision of the Cardiac arrest database of matched controls (single data transfer) to the 
Chief Investigator after the end of the study recruitment will only include anonymised data, and 
data will be transferred between nhs.net emails to ensure data protection and confidentiality. Any 
missing data will be queried with the host establishment by the LAS team. 
13.4 Record Retention and Archiving 
The Trial Master File will be stored securely for a minimum of 20 years after the study end (Section 
7.9) and in accordance with the CVCTU’s Standard Operating Procedure. The Chief Investigator 
will be responsible for the security of the data but may delegate this to any storage repository, 
approved by the JRMO. 
All electronic copies of data will be deleted two years after publication of the study (Section 8.9). 
The UK Policy Framework for Health and Social Care Research requires that research records 
are kept for 20 years after the project has completed. For studies sponsored by Barts Health NHS 
Trust the approved repository for long-term storage of local records is the Trust Corporate Records 
Centre. All research documentation must be archived in physical form – source data collected 
electronically will be printed and certified as authentic by the investigators. Electronic archiving is 
not accepted.  
14. Laboratories 
14.1 Central and local laboratories 
The central laboratories for Barts Health NHS Trust will provide haematological, coagulation and 
biochemical assessments outlined in Table 2. The central and satellite Haematology, Blood 
Coagulation and Clinical Biochemistry laboratories have Certificates of Accreditation with Clinical 
Pathology Accreditation (UK) Ltd. The laboratories are also registered with UK National External 
Quality Assessment Services (UK NEQAS).  

                                  
 
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14.2 Sample collection, preparation and procedures 
Blood samples will be taken as part of routine clinical practice. Therefore they will be requested, 
sampled, labelled and analysed according to the practices and policies at Barts Health NHS Trust 
for all clinical samples. 
14.3 Sample storage and transfer 
Excess serum and plasma are stored by the laboratories routinely for seven days to facilitate 
additional tests or confirmatory tests. These samples are stored at -20°C in the clinical 
laboratories.  After the usual retention period for the clinical laboratories the excess serum and 
plasma will be transferred to the study team. Thereafter samples will be stored at -80°C. Samples 
will be labelled with the study ID and no patient identifiers. The chain of custody will be recorded 
in the Investigator Site File according to the study Standard Operating Procedures (Table 4). 
Subsequent analysis of these samples will require appropriate research approvals to be in place. 
All samples will be destroyed using standard laboratory procedures after 3 years. 
15.  Interventions and tools 
15.1 Devices 
The CARDIOHELP-i ECMO device (Maquet, Rastatt, Germany) is a CE marked device with an 
intended purpose which encompasses this investigation (see Table 6). Therefore, the Medicines 
and Healthcare products Regulatory Agency does not need to notified about this study. 
The CARDIOHELP-i device is classified in accordance with Council Directive 93/42/EEC 
concerning medical products, Appendix IX as a Class IIb device. It is defibrillator-protected Type 
CF in accordance with IEC 60601-1. 
All devices will be submitted to Clinical/Medical Physics, Barts Health NHS Trust, for assessment 
according to the Trust policy on the management of medical equipment (CLI/POL/151/2014-001 
or any superseding version). 
The device will be used with an HLS Set Advanced 7.0 disposable. This is delivered sterile and 
pyrogen-free. It is stored in a cool, dark and dry place between 10-30 °C. 
Table 6 Intended purposes of the CARDIOHELP-i (Maquet) 
Purpose 
Description 
Intended use 
To drive, control, monitor and record an extracorporeal circulation 
For intra-hospital and inter-hospital patient transportation and for continuous operation 
Intended user 
Trained specialist medical staff 
Intended patients 
All patients independent of age, size and weight 
Intended environments 
Operating rooms, catheter laboratories, emergency departments and intensive care 
units 
In addition, the CARDIOHELP System can be used for intra-hospital and inter-hospital 
patient transportation in vehicles such as ambulances and aircraft as well as for 
emergency use outside a clinical environment 
Taken from the Instructions for Use, Revision 1.5, Issued October 2014 
15.2 Techniques and interventions 
The suggested specific techniques for pre-hospital ECMO are outlined in the latest version of the 
Study Manual. This details: 
• Team composition 
• Daily checks and team preparedness 
• Dispatch of the ECMO team 
• Initial patient assessment 
• Priming of the ECMO circuit 
• Insertion of guidewires into the femoral vessels 
• 20 minute time out procedure 

                                  
 
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• Cannulation of the femoral vessels and commencement of ECMO 
• Post ECMO/ROSC care including transfer to the Heart Attack Centre 
• Care at the Heart Attack Centre 
15.3 Tools 
15.3.1 
EQ-5D-5L 
The EQ-5D-5L questionnaire will be used to assess quality of life in patients at 3 months [23]. This 
is a validated questionnaire and a license to deliver this questionnaire has been granted. 
Instructions for the use of this instrument are outlined in a trial Standard Operating Procedure 
(Table 4) to minimise inter-observer variations. We may administer the questionnaire using the 
usual ICU video-conference clinic, which has been established following the COVID-19 pandemic 
to reduce the need for vulnerable patients to travel to the hospital. 
15.3.2 
Modified Rankin Scale of neurological assessment 
The modified Rankin Scale will be used to assess neurological disability in patients at hospital 
discharge and 3 months [24]. Instructions for the use of this instrument are outlined in a trial 
Standard Operating Procedure (Table 4) to minimise inter-observer variations. We may administer 
the questionnaire using the usual ICU video-conference clinic, which has been established 
following the COVID-19 pandemic to reduce the need for vulnerable patients to travel to the 
hospital. 
15.3.3 
Functional independence measure 
The Functional Independence Measure is an internationally validate tool that will provide a detailed 
assessment of patients’ functional status over the domains of self-care, sphincter control, 
transfers, locomotion, communication and social cognition [25]. Assessors will have undergone 
specific training in the use of the instrument and will follow the trial Standard Operating Procedure 
for its use (Table 4) to minimise inter-observer variations. We may administer the questionnaire 
using the usual ICU video-conference clinic, which has been established following the COVID-19 
pandemic to reduce the need for vulnerable patients to travel to the hospital. 
15.4 Non-investigational medicinal products (NIMPs) 
The non-investigation medicinal products used in the study are outlined in Table 7. Many other 
drugs may be used in the care of the patient as dictated by the attending clinicians. 
Table 7 Non-investigational medicinal products 
Medicinal product 
Comments 
Storage requirements 
Oxygen/Medical air mixture 
Sweep gas for ECMO circuit 
Keep away from extremes of 
heat 
Rocuronium bromide 
As neuromuscular blockade  
2-8°C 
Teicoplanin 
As antibiotic prophylaxis for surgical site infection 
None 
Heparin sodium 
As an anticoagulant for ECMO 
Below 25°C 
Compound sodium lactate 
For priming of the ECMO circuit 
None 
The pre-mixed oxygen/medical air mixture will be prepared as a special gas by the British Oxygen 
Company. It will be stored in accordance with the Health Technical Memorandum 02-01: Medical 
gas pipeline systems (Part B Operational management) produced by the Department of Health 
and outlined in the trial Standard Operating Procedure for the Management of medical gases. 
Specifically, a suitable storage area (BNB_06_071 in King George V Building, St Bartholomew’s 
Hospital) has been approved by the trial pharmacist. A chain of custody will be maintained for all 
non-investigation medicinal products. A Summary of Product Characteristics (SPC) for each NIMP 
will be stored in the Trial Master File. The Undesired Effects outlined in these SPC will act as 
Reference Safety Information to enable attribution of causality and expectedness when classifying 
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16. Safety reporting  
16.1 Adverse Events (AEs) 
An AE is any untoward medical occurrence in a participant to whom an intervention has been 
administered, including occurrences which are not necessarily caused by or related to that 
intervention. An AE can therefore be any unfavourable or unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with study activities. 
16.2 Adverse Reaction (ARs)  
An AR is any untoward and unintended response in a participant to an intervention.  All adverse 
events judged by either the reporting investigator or the sponsor as having a reasonable causal 
relationship to the intervention qualify as adverse reactions. The expression ‘reasonable causal 
relationship’ means in general that there is evidence or an argument to suggest a causal 
relationship. 
16.3 Classification of Adverse Events and Reactions 
A serious adverse event (SAE) is defined as an untoward occurrence that: 
• Results in death, 
• Is life-threatening, 
• Requires hospitalisation or prolongation of existing hospitalisation, 
• Results in persistent or significant disability or incapacity, 
• Consists of a congenital anomaly or birth defect, or 
• Is otherwise considered medically significant by the investigator. 
All Serious Adverse Events will be assessed for causality and expectedness, using the definitions 
in Table 8 and Table 9. Reference Safety Information for this assessment is included in Table 9 
and Summary of Product Characteristics for the NIMPS outlined in Table 7. 
Table 8 Definitions of relationship of an SAE to study intervention 
Relationship 
Definition 
Unrelated 
There is no evidence of any causal relationship 
Related, 
Unlikely 
There is little evidence to suggest there is a causal relationship (e.g. the event did not occur 
within a reasonable time after administration of the trial medication). There is another 
reasonable explanation for the event (e.g. the patient’s clinical condition, other concomitant 
treatment). 
Possibly 
There is some evidence to suggest a causal relationship (e.g. because the event occurs 
within a reasonable time after administration of the trial medication). However, the influence 
of other factors may have contributed to the event (e.g. the patient’s clinical condition, other 
concomitant treatments). 
Probably 
There is evidence to suggest a causal relationship and the influence of other factors is 
unlikely. 
Definitely 
There is clear evidence to suggest a causal relationship and other possible contributing 
factors can be ruled out. 
Not assessable 
There is insufficient or incomplete evidence to make a clinical judgement of the causal 
relationship. 
 
 
 
 
 
Table 9 Definitions of expectedness of an SAE for the study intervention 
Expectedness 
Definition 
Unexpected 
Unexpected events are those not anticipated but could relate to the study. Events that are of a 
more serious form that would be expected should also be considered as unexpected. 

                                  
 
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Expected 
Expected events are: 
-Failure to cannulate a patient for ECMO 
-Hypoxic brain injury 
-Death due to myocardial failure 
-Death due to hypoxic brain injury 
-Vascular damage during cannulation in adverse environment 
-Bleeding at site of cannulation 
-Infection at site of cannulation 
-Intracranial haemorrhage 
-Gastrointestinal haemorrhage 
-Events outlined in the Undesired Effects section of the SPC for each NIMP 
 
16.4 Notification and reporting of Adverse Events and Reactions 
If the AE is not defined as serious (see Section 16.3), the AE will be recorded in the study 
documents, and the participant followed up by the research team. The AE will be documented in 
the participants’ source documents, the electronic Case Report Form (CRF) in REDCap, and, 
where appropriate, medical records. 
Medical judgement will be exercised in deciding whether an AE is serious in other situations. 
Important AEs that are not immediately life-threatening or do not result in death or hospitalisation 
but may jeopardise the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above, should also be considered serious. 
16.5 Notification and reporting of Serious Adverse Events 
SAEs will be reported to the REC where in the opinion of the Chief Investigator the event was 
serious and: 
• Related (it may have resulted from administration of any of the research interventions), and 
• Unexpected (the type of event is not listed in Table 9). 
All SAEs will be reported to the CVCTU within 24 hours of site notification via the REDCap SAE 
eCRF, and will be recorded in the study SAE log and will constitute part of the routine statutory 
safety reporting to the Research Ethics Committee (REC). Serious Adverse Events (SAEs) that 
are considered to be ‘related’ and ‘unexpected’ will be reported to the sponsor within 24 hours of 
learning of the event, and to the REC within 15 days in line with the required timeframe. Any 
additional relevant information must be reported within 8 days of sending the first report. 
16.6 Urgent Safety Measures 
The CI will take urgent safety measures if necessary to ensure the safety and protection of the 
clinical study participant from immediate hazards to their health and safety. The measures will be 
taken immediately. The approval of the REC prior to implementing urgent safety measures is not 
required. However, the CI will inform the sponsor and Research Ethics Committee (via telephone) 
of this event immediately.  
The CI will inform the REC in writing within 3 days, in the form of a substantial amendment. The 
sponsor (Joint Research Management Office (JRMO)) will be sent a copy of the correspondence 
with regards to this matter.  
16.7 Annual Safety Reporting 
The CI will send the Annual Progress Report to the REC using the HRA template (the anniversary 
date is the date on the REC “favourable opinion” letter) and to the sponsor.  
16.8 Overview of the Safety Reporting responsibilities 
The CI is the medical assessor on behalf on the sponsor and will review all events reported. The 
CI will ensure that safety monitoring and reporting is conducted in accordance with the sponsor’s 
requirements.  
The CVCTU will have oversight of safety reporting, and will monitor the study to ensure all SAEs 
are identified and reported in the required timelines to the Sponsor and REC as required. 

                                  
 
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17. Monitoring and auditing 
The sponsor or delegate retains the right to audit any study, study site, or central facility. Any part 
of the study may be audited by the funders, where applicable.  
The CVCTU will monitor the study, with reference to both the CVCTU’s Standard Operating 
Procedure and following the study specific monitoring plan. Monitoring will be conducted to ensure 
data integrity and patient safety, as well as compliance to the protocol and GCP. Both on-site visits 
and central monitoring of data via the REDCap database will be performed. Monitoring reports will 
be written and made available to the Sponsor. Monitoring will include source data verification, 
query resolution and review of GCP and protocol compliance. Protocol deviations will be logged 
in the Trial Master File and be reported to the Chief Investigator and Sponsor. Frequently recurring 
breaches are not acceptable and will require immediate action to prevent the variations. 
The Joint Research Management Office (JRMO) of Barts Health NHS Trust may audit the study 
to determine whether the trial related activities were conducted, and that data were recorded, 
analysed and accurately reported according to the protocol, CVCTU's Standard Operating 
Procedures and Good Clinical Practice (GCP). Audits will be triggered: 
• if the JMRO's identifies a need during the risk assessment process. 
• following an allegation of research misconduct or fraud or a suspected breach of regulations 
• at random 
18. Trial committee and investigator arrangements 
18.1 Trial steering committee (TSC) 
A Trial Steering Committee will be constituted and will be chaired by an independent expert. It will 
be set up and run according to the principles outlined in the CVCTUs Standard Operating 
Procedure. Terms of reference (TOR) for committees will be agreed before the commencement 
of the trial. All members of committees must agree and sign the TOR before recruitment into the 
trial begins. Meetings will be formally minuted with actions recorded and stored in the Trial Master 
File. 
The TSC will provide oversight to the conduct of the study on behalf of the study Sponsor and 
Funder. 
The TSC will meet at least after the first two patients are recruited or at least every 6 months either 
face to face or by teleconference. Meetings will be scheduled in parallel with the DSMC meetings, 
typically following the DSMC. Observers from the Sponsor and Funder will be invited and may be 
in attendance. 
18.2 Data Safety and Monitoring Committee (DSMC) 
A Data Monitoring and Safety Committee will be constituted that will be chaired by an independent 
expert. It will be set up and run according to the principles outlined in the CVCTU’s Standard 
Operating Procedure. Terms of reference (TOR) for committees will be agreed before the 
commencement of the trial. All members of committees must agree and sign the TOR before 
recruitment into the trial begins. 
The DSMC will be responsible for: 
• monitoring any trial data 
• making recommendations to the TSC on whether there are any ethical or safety reasons 
why the study should not continue 
• advising the TSC regarding the release of data and/or information 
• consider data emerging from other studies. 
The DSMC will meet after the first two patients are recruited or at least every 6 months either face 
to face or by teleconference. Additional meetings may be convened at the request of the DSMC 

                                  
 
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or if there are any safety concerns. Observers from the Sponsor and Funders will be invited and 
may be in attendance. 
18.3 Investigators 
The investigators are responsible for ensuring that the study is conducted according to this 
protocol and any applicable regulations. 
All investigators will have undergone a training program that aims to provide each investigator with 
a thorough working knowledge of the protocol, study manual, associated standard operating 
procedures and applicable regulations and competence to perform their specific roles. The specific 
requirements are outlined in the latest version of the Study Training Manual. 
All investigators will have undergone Good Clinical Practice training in the previous two years and 
will renew this appropriately.  
The Chief Investigator will ensure that the study records are complete, accurate and current. 
These records will include the following materials: 
• Correspondence with the Sponsor, the Trial Steering Committee, the investigators, the 
funders and the Research Ethics Committee (REC). 
• Accountability of records of receipt, use, and disposition of all investigational devices and 
study materials, including the type and quantity, date of receipt, any serial/batch number and 
the names of all persons receiving, using and disposing of such items 
• Study Subject Records, including Informed Consent forms, copies of all completed Subject 
Case Report Forms (CRFs) and supporting documents (laboratory reports and reports of 
diagnostic tests, medical records, etc.). 
• All relevant observations, including records concerning adverse events (whether anticipated 
or unanticipated) 
• Current study protocol and protocol deviation log, with dates and details of any reason for 
deviations from the protocol that could affect the scientific quality of the study or the rights, 
safety, or welfare of the subjects 
• The approved blank Informed Consent form and blank Subject CRFs 
• Certification that the Protocol has been approved by all of the necessary approving 
authorities 
• Signed Investigator's Agreements with curricula vitae of all participating Investigators 
The Chief Investigator will be responsible for the following reports: 
• Serious adverse events 
• Deviations from the investigational plan 
• Annual progress reports to the study Sponsor, Funders and REC. 
• Final report to the study Sponsor, Funders and REC. The end of study declaration will be 
made to the REC within 90 days of the end of the study, and the end of study report will be 
submitted within 1 year of the end of study. This will be produced irrespective of whether the 
study finishes as scheduled or is terminated early. 
 
19. Finance and funding 
This study is funded by: 
• 
London’s Air Ambulance Charity through an unrestricted research grant 
• 
Barts Charity through an unrestricted research grant 
• 
Maquet Cardiopulmonary GmbH through unrestricted funding that provides free ECMO 
disposables to the study. 

                                  
 
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20. Indemnity 
The NHS indemnity scheme will apply. It provides cover for the design, management, and conduct 
of the study. 
21. Dissemination of research findings 
A manuscript summarising the study will be drafted by the chief investigator following completion 
of the study. It will be formulated according to the Consolidated Standards of Reporting Trials 
(CONSORT) guidelines and the Template for Intervention Description and Replication (TIDieR) 
checklist and guide [26, 27] The chief investigator will be responsible for the integrity of the data 
contained within the manuscript and accuracy of the analysis. All investigators will have full access 
to the data and provide interpretation and critical revision of the manuscript. Any funders will have 
no role in the preparation, review or approval of the manuscript. 
Authorship credit will be according to internationally agreed guidelines (www.icmje.org) that 
require authors to fulfil all of the following criteria: 
• substantial contributions to the conception and design, or acquisition of data, or analysis and 
interpretation of data 
• drafting the article or revising it critically for important intellectual content 
An electronic version of published research papers will be made freely available in Europe 
PubMed Central as soon as possible and definitely within 6 months of publication. We will share 
an electronic version of the manuscript with patients who participated in the study and any patients 
and publics involved in the study design and conduct. 
Any results communicated via the press, social media or internet will be done following 
consultation and agreement of the press officers of Barts Health NHS Trust and the funders. 
All research participants will be informed of the results via letter with 6 months of the study ending. 
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