Title: Carbon Dioxide Insufflation and Brain Protection During Open Heart Surgery. A Randomized Controlled Trial (CO-Two)
Funder: Medical Research Council

Abstract: Brain injury is a major 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 and may increase the risk of developing dementia._x000D_ Surgeons believe that the brain injury results from microscopic air bubbles that enter the bloodstream when the heart is opened up during surgery. These air bubbles are carried to the brain where they can get stuck in the small blood vessels causing damage. One way that surgeons think they can reduce the number of air bubbles 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. _x000D_ We want to conduct a study known as a randomised controlled trial, in which we will randomly divide patients who are undergoing surgery to repair or replace one or more of their heart valves into two groups; one group will receive carbon dioxide gas blowing into the heart and the other group will receive medical air (placebo). The 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 then have a very sensitive brain scan 7-10 days after their surgery (magnetic resonance imaging, or MRI). This is safe and should take no more than 30 minutes. Participants will also complete questionnaires to assess brain function and quality of life before their operation 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. _x000D_ We hope to recruit 704 patients from 8 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 carbon dioxide does lead to fewer air bubbles and whether fewer air bubbles means less damage to the brain. We will ask some patients taking part (about 100) to have an extra test during their surgery. They will have an ultrasound scan of the main artery going to their head during their operation. The test is safe and will not delay the operation. The scan will allow the number of air bubbles to be counted using a computer. This information can be added to the brain scan to see if the patients with fewer bubbles have fewer areas of damage in their brains._x000D_ We have cardiac surgeons, an anaesthetist, brain MRI experts, and experts in clinical trials on the team. We have also consulted with our patient advisory group (patients who have undergone heart surgery) and described our study to them. Patients were reassured that the brain scans are safe and that they happen during the hospital stay. They also did not mind performing memory tests but indicated that those before the operation should be done at pre-operative assessment rather than when they come in for surgery, to avoid extra burden on patients who are worried about a major operation.

Lay abstract: Background: Brain injury, in the form of stroke, delirium or cognitive dysfunction, is common after cardiac surgery. It is assumed to be triggered by the release of trapped air bubbles (microemboli) into the blood steam, which form when the heart is opened and then closed. Carbon dioxide insufflation (CDI) is widely used to displace air bubbles during surgery, but there is little evidence that it prevents brain injury._x000D_ Aim: To evaluate the efficacy and safety of CDI compared with medical air insufflation in patients undergoing open heart valve surgery._x000D_ Study design: Multicentre, placebo-controlled RCT with blinding of participants and all clinical staff except the perfusionist responsible delivering the study intervention, and an internal pilot to determine the feasibility of recruitment and adherence to the protocol._x000D_ Population: Adults aged = 50 years undergoing left side heart valve repair or replacement surgery via a partial or full sternotomy using central aortic perfusion cannulae_x000D_ Exclusion criteria: contraindication to MRI or CDI_x000D_ Interventions: CDI: CO2 insufflation (5.0 L/min); Placebo: Medical air insufflation (5.0 L/min)_x000D_ Outcome measures: Primary: acute ischemic brain injury based on new brain lesions identified with standardised diffusion weighted imaging (DWI) between 5 and 10 days postoperatively or clinical evidence. _x000D_ Secondary: number and volume of DWI brain lesions; impairment caused by brain injury (NIH stroke scale assessed preoperatively, days 1, 3, and 7 and 3m); delirium (3-minute diagnostic interview for Confusion Assessment Method, assessed preoperatively and days 1, 3, and 7); functional status (modified Rankin scale; Barthel index; geriatric depression scale); neurocognitive function (verbal and visual memory, executive functioning, visuospatial or constructional praxis, attention, and information processing speed); quality of life (SF-12) all assessed preoperatively and at 3m, composite of all-cause mortality, stroke, or acute kidney injury within 30 days; survival to 3m; serious adverse events._x000D_ Sample Size: 704 participants (352 per group) which will provide 90% power to detect a 25% relative reduction in the incidence of brain injury, assuming a 48% rate in the placebo group with 5% statistical significance (2-sided)._x000D_ Mechanistic sub-study: In 100 patients from the Bristol centre, we will investigate the association between gaseous cerebral microemboli detected using transcranial doppler ultrasound (TCD) and new brain lesions identified with DWI and whether CDI reduces microembolic load. Cerebral blood flow measured with TCD and tissue oxygen index of the frontal lobes measured using near-infrared spectroscopy will also be analysed._x000D_ Project timetable including recruitment rate: The study will aim to recruit an average 3-4 patients/centre/month. Study duration 41m: 8m set-up; 24m recruitment (7m pilot and 17m main trial); 3m follow-up on all participants; 6m analysis and report._x000D_ Team expertise: The project team includes cardiac surgeons, methodologists, anaesthetists and neuroimaging experts. The study has been presented to the Bristol Cardiovascular patient advisory group, who helped with the design._x000D_ Dissemination: The research will be published in peer-reviewed journals, presented at national and international conferences and will be disseminated among members of national and international cardiothoracic societies. Our patient advisory group will advise on dissemination to relevant patient groups

Research activity codes: 5.7 PHYSICAL;6.7 PHYSICAL
Health categories: CARDIOVASCULAR;NEUROLOGICAL