Impact of Remote Ischemic Preconditioning Preceding Coronary Artery Bypass Grafting on Inducing nEuroprotection

Coronary artery bypass grafting (CABG) is very effective in the management of complex coronary artery disease (CAD). Cardiopulmonary bypass (CPB) is commonly employed to achieve a still and bloodless field, which facilitates the creation of technically impeccable coronary anastomoses. Multiple adverse effects that stem from exposure of blood to a non-endothelial surface contrast the clear benefit of CPB. Neurological damage remains one of the most dreaded complications following CABG. While the incidence of new focal motor deficits is low, postoperative neurocognitive dysfunction (POCD) is seen commonly. The increasing risk profile of contemporary CABG patients makes neuroprotective strategies progressively more important.

Ischemic preconditioning is an endogenous protective response triggered by brief episodes of nonlethal ischemia and reperfusion. In clinical practice remote ischemic preconditioning (RIPC) is achieved by inducing short periods of ischemia of the upper extremity, followed by restitution of flow. This non-pharmacological strategy for inducing ischemic tolerance is cost-free and non-invasive, with potentially wide clinical applicability.

The "Impact of Remote Ischemic Preconditioning preceding Coronary Artery bypass Grafting on inducing nEuroprotection (RIPCAGE) trial" will recruit 70 patients scheduled for elective CABG at a single academic center. The hypothesis tested in this research proposal is that RIPC will decrease the extent of postoperative neuronal damage and lead to a reduction in POCD among CABG patients. Specifically, the investigators aim to determine whether RIPC can reduce magnetic resonance imaging (MRI) detectable brain damage and attenuate the neurocognitive decline universally seen in patients after CABG.

The primary composite outcome will consist of a composite of new ischemic lesions on brain MRI and POCD.

The secondary endpoints will be the following:

• Brain connectivity profiles on resting-state functional MRI (rs-fMRI).
• Pooled ischemic volumes of new diffusion-weighted imaging (DWI) hyperintensity.
• Percent declines of components in individual neurocognitive tests.

Patients will be randomly allocated in a 1:1 ratio to either receive RIPC or no intervention (control group). In the intervention arm, transient upper extremity ischemia will be induced after induction of anesthesia by inflating a blood pressure cuff to 200 mmHg for 5 min, followed by a 5 min cuff deflation. This sequence will be repeated 3 times. Patients in the control group will also have a blood pressure cuff placed, but it will not be inflated. All patients will undergo preoperative neurocognitive testing coupled with baseline brain MRI. The neurocognitive evaluation will consist of the Montreal Cognitive Assessment (MoCA) test and the Trail Making Test (TMT). Decreased cognitive function for each test will be defined as an individual decrease of at least 1 standard deviation of the group baseline mean for that test. POCD will be defined as a decrease in two or more tests. The patients will have a repeat neurocognitive evaluation prior to discharge from hospital.

Standard MRI sequences will be performed in all patients. DWI will be utilized for volumetric analysis of brain tissue exhibiting stigmata of ischemic injury. The timing of apparent diffusion coefficient quantification will be standardized to postoperative day 7, as it normalizes over time. Additional MRI sequences will include susceptibility weighted imaging (SWI) and diffusion tensor imaging (DTI). Resting state functional MRI will be performed in order to investigate the coordination of activity across brain networks. Pre- and postprocedural rs-fMRI data will be subsequently compared with each other. Disruption in the connectivity of neural circuits induced by the operation will be thereby be objectivized.

Patients will be followed for a total of 3 months, during which time all adverse events will be recorded and adjudicated by an independent clinical events committee.

Inclusion criteria

• Adult patients with multi-vessel coronary artery disease undergoing primary, elective on-pump CABG
• Written informed consent

Exclusion criteria

• Prior stroke, transient ischemic attack or reversible ischemic neurologic deficit
• Stenosis of the internal carotid artery (>50%)
• Significant peripheral arterial disease affecting the upper limbs
• Acute coronary syndrome within 30 days prior to surgery
• Inability to provide consent
• Postoperative exclusion criteria will be limited to contraindications to follow-up MRI (such as pacemaker dependence)