Condition category
Surgery
Date applied
11/05/2020
Date assigned
14/07/2020
Last edited
14/07/2020
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Background and study aims
Brain injury is a common complication after heart surgery. It affects about 6 in every 10 people who undergo open heart surgery. The injury can be severe, for example stroke, although this is rare. In most people the injury is milder, manifesting as problems with memory and thinking. In some patients, these problems can persist for up to one year after heart surgery and may increase the risk of developing dementia. Surgeons believe that brain injury results from microscopic air bubbles (microemboli) that enter the bloodstream when the heart is opened during surgery. These air bubbles are carried to the brain where they can get stuck in the small blood vessels and prevent blood from reaching that area of the brain, damaging, and eventually killing, surrounding nerve cells. One way that surgeons think they can reduce the number of air bubbles entering the bloodstream is by gently blowing the gas carbon dioxide into the area they are operating on. Carbon dioxide dissolves in blood much more easily than air, so it can displace air bubbles. However, there is little evidence that this technique, known as carbon dioxide insufflation (CDI), prevents brain injury after cardiac surgery. The CO2 study will test the hypothesis that CDI prevents brain injury in patients undergoing heart surgery.

Who can participate?
Adults aged ≥ 50 years with planned left side aortic or mitral valve surgical repair or replacement.

What does the study involve?
Patients who are undergoing surgery to repair or replace one or more of their heart valves will be randomised into two groups; one group will receive carbon dioxide gas blowing into the heart and the other group will receive medical air (placebo). Medical air has no effect on the amount of air entering the bloodstream. Neither surgeons nor participants will know which type of gas is being used; only the person operating the cylinder will know. Everything else about the operation will be exactly the same. Participants will have a very sensitive brain scan between 2 and 10 days after their surgery (diffusion weighted magnetic resonance imaging, or DW MRI). This is safe and should take no more than 30 minutes. Participants will also complete tests and questionnaires to assess brain and physical function and their quality of life before and 3 months after the operation. We will also collect information about how the operation went and any complications that the patients experience during and after the surgery, for example, strokes and kidney damage. We hope to recruit 704 patients from at least eight UK NHS cardiac surgery centres into the trial. The trial is expected to take about 3 and half years to complete. We also want to do a small sub-study within the trial to determine whether CDI does lead to fewer air bubbles entering the circulation and whether fewer air bubbles means less damage to the brain. We will ask 100 patients taking part at the Bristol centre to have an ultrasound scan of the main artery going to their head during their operation. The ultrasound scan is safe and will not delay the operation. The scan will allow the number of air bubbles entering the blood stream to be counted using a computer. This information can be reviewed against the brain scan to see if patients with fewer bubbles have fewer areas of damage in their brains.

What are the possible benefits and risks of participating?
None

Where is the study run from?
Bristol Royal Infirmary (UK)

When is the study starting and how long is it expected to run for?
October 2019 to May 2023

Who is funding the study?
National Institute for Health Research (NIHR) (UK)

Who is the main contact?
Rachel Todd, CO2-trial@bristol.ac.uk

Trial website

Contact information

Type

Public

Primary contact

Ms Rachel Todd

ORCID ID

Contact details

Bristol Trials Centre Clincial Trials and Evaluation Unit
Level 7 Queen’s Building
Bristol Royal Infirmary
Upper Maudlin Street
Bristol
BS2 8HW
United Kingdom
01173422526
CO2-trial@bristol.ac.uk

Additional identifiers

EudraCT number

2020-001322-54

ClinicalTrials.gov number

Nil known

Protocol/serial number

CS/2018/6632, IRAS 278171, CPMS 45760

Study information

Scientific title

Carbon dioxide insufflation and brain protection during open-heart surgery: a randomised controlled trial

Acronym

CO2

Study hypothesis

In patients undergoing open heart valve surgery via partial or full sternotomy, CDI plus standard de-airing is protective against ischaemic brain injury caused by cerebral embolisation (air microemboli) compared with medical air insufflation (placebo) plus standard de-airing.

Ethics approval

Approval pending, East Midlands and Nottingham 2 REC (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS, UK; +44 (0)207 104 8103; nottingham2.rec@hra.nhs.uk), ref: 20/EM/0130

Study design

Multicentre placebo-controlled randomized controlled clinical trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Prevention

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

Brain injury following open-heart valve surgery

Intervention

Participants will be randomised in a 1:1 ratio (stratified by type or procedure and centre) to receive either carbon dioxide insufflation (IMP) or medical air insufflation (placebo).
Insufflation with the allocated intervention will be delivered at a flow rate of 5L/min from just before cannulation for cardiopulmonary bypass until 10 minutes after cardiopulmonary bypass.
Participants will be followed up until they are discharged and again at three months.

Intervention type

Other

Phase

Drug names

Primary outcome measure

Acute ischemic brain injury within 10 days post-surgery based on new brain lesions identified with DW MRI or clinical evidence of permanent brain injury according to the updated definition of stroke for the 21st century

Secondary outcome measures

1. Number and volume of DWI brain lesions measured using the DW MRI conducted for each participant between 2-10 days post-surgery
2. Objective quantification of the impairment caused by new ischemic brain injury assessed using the National Institutes of Health Stroke Scale at pre-surgery, day 3 and three months post-surgery
3. Delirium assessed using the 3-minute diagnostic interview for Confusion Assessment Method at pre-surgery, day 3 and three months post-surgery
4. Functional status assessed using the Barthel Index score at pre-surgery and three months post-surgery
5. Neurocognitive function assessed at pre-surgery and three months post-surgery using the following tests:
5.1. Addenbrooke’s Cognitive Examination III
5.2. Trail making Tests A and B
6. Quality of life assessed using the 12-Item Short-Form Health Survey (SF-12) at pre-surgery and three months post-surgery
7. Composite of all-cause mortality, clinical stroke, or acute kidney injury within 30 days of surgery, by review of participants medical notes
8. Serious adverse events (SAEs) to 3 months, by review of participants medical notes and discussion with the participant at the three month post-surgery follow up visit
9. Survival to 3 months by review of the participants medical notes and attendance at the three-month post-surgery follow up visit

Overall trial start date

01/10/2019

Overall trial end date

01/05/2023

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Age ≥ 50 years
2. Planned left side aortic or mitral valve surgical repair or replacement (with or without another procedure, e.g. coronary artery bypass graft) via a partial or full sternotomy using central aortic perfusion cannulae

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

704

Participant exclusion criteria

1. Contraindication to medical carbon dioxide: acquired or genetic of acidosis (i.e. renal tubular acidosis)
2. Contraindication to MRI (e.g. known intolerance, permanent pacemaker in situ or expected implantation of a permanent pacemaker)
3. History of clinical stroke within 3 months prior to randomisation
4. Cardiac catheterisation within 3 days of the planned surgery
5. Cerebral and/or aortic arch arteriography or interventions within 3 days of the planned surgery
6. Active endocarditis at time of randomisation
7. Planned concomitant aortic procedure such as root replacement
8. Clinical signs of cardiogenic shock or treatment with IV inotropic therapy prior to randomisation
9. Participation in an interventional (drug or device) trial
10. Unable to provide written informed consent
11. Prisoners

Recruitment start date

01/09/2020

Recruitment end date

31/08/2022

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Bristol Royal Infirmary
University Hospitals Bristol and Weston NHS Foudnation Trust Marlborough Street
Bristol
BS1 3NU
United Kingdom

Sponsor information

Organisation

University Hospitals Bristol NHS Foundation Trust

Sponsor details

Research & Innovation Department
Level 3
Education Centre
Upper Maudlin Street
Bristol
BS2 8AE
United Kingdom
+44 (0)1173420233
R&Dsponsorship@uhbw.nhs.uk

Sponsor type

Hospital/treatment centre

Website

http://www.uhbristol.nhs.uk/

Funders

Funder type

Government

Funder name

National Institute for Health Research

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Planned dissemination of study results via scientific journals, conference presentations and a study website.

IPD sharing statement:
The datasets generated during and/or analysed during the current study are available upon request from the sponsor, after publication of the main result of the study. Thereafter, anonymised data will be made available for secondary research, conditional on assurance the proposed use of the data is compliant with MRC Policy on Data Sharing regarding scientific quality, ethical requirements and value for money.

Intention to publish date

31/05/2023

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

13/05/2020: Trial’s existence confirmed by National Institute for Health Research (NIHR).