Remote Ischemic Preconditioning for Carotid Endarterectomy (RIP-CEA)

This is a randomized controlled trial designed to test an intervention (Remote ischemic preconditioning) in patients undergoing carotid endarterectomy (CEA) for carotid artery stenosis (CAS). The outcomes of interest include neurocognitive function, cardiac complications, and biomarkers of brain ischemia.

Multiple large, high quality randomized trials have shown carotid endarterectomy (CEA) is effective in decreasing future risk of stroke in patients with carotid artery stenosis. Outcomes after carotid endarterectomy have improved over time. The major risks including stroke and myocardial infarction (MI) are rare (<3% stroke and 4% for MI. However, subtle degrees of cerebral ischemia and myocardial injury are more common. Research is now focused finding ways to reduce these subclinical adverse effects of CEA. Due to its high metabolic activity, the brain is especially vulnerable to periods of ischemia during carotid cross clamping. Ischemic tolerance has been demonstrated after direct ischemic conditioning in the brain. However, direct conditioning is difficult and potentially dangerous when is comes to carotid interventions making remote ischemic preconditioning an attractive alternative. In animal models, remote ischemic preconditioning (RIPC) has been shown to produce an equivalent response to direct neuronal conditioning at the cellular level. The precise mechanisms underlying the phenomenon of RIPC have yet to be fully elucidated. However, It is likely that both neural and humoral mechanisms are at play. Multiple studies have shown decreased levels of inflammatory markers in brains of animal models undergoing RIPC and then middle cerebral artery occlusion. There has only been one study of RIPC in carotid endarterectomy so far. Patients were randomized to 10 min ischemia on each leg prior to clamping the carotid. Primary outcome was significant postoperative deterioration in saccadic latency determined by quantitative oculometry (time taken to respond and fix on a visual stimulus that appears suddenly). Additionally, troponins were drawn up to 48 hours post operatively. There was deterioration in quantitative oculometry in 8/25 RIPC and 16/30 control (p=0.11) and no difference in troponins. However this was a small number of patients. Major clinical events such as stroke or MI are uncommon following CEA. This hampers the assessment of new, novel interventions as any trial would require several thousand patients to detect a useful clinical effect. The only alternative is to use surrogate end points to obtain "proof of concept" justifying larger trials. Several serum markers of neuronal damage such as S100-beta and neuron-specific enolase have been identified but are not reliable or specific enough to be used clinically. Another surrogate that is directly related to the concept of subtle degrees of neuronal ischemia occurring during CEA is neurocognitive function. 20-25% of patients have been shown to experience significant cognitive decline following CEA. This has been correlated with findings of ischemia on diffusion weighted MRI in patients after CEA indicating that local ischemia and microemboli are responsible for this decline. Thus, neurocognitive testing before and after carotid revascularization may be an ideal surrogate end point to study in remote ischemic preconditioning and it's potential to mediate the subtle degree of neuronal ischemia produced during carotid revascularization. However, neurocognitive function is also an endpoint with clinical relevance to patients. This study will be a double armed randomized trial. The treatment arm will be Remote ischemic preconditioning and the Control arm will be Usual care. Intervention allocation ratio will be 1:1 RIPC:usual care. Randomization strategy will be a using a 1:1 fixed block of 4 randomization stratified by symptom status and age. Those randomized to RIPC will undergo a standard protocol of 4 cycles of 5 minutes of forearm ischemia with 5 minutes of reperfusion requiring 35 minutes for an application. Forearm ischemia will be induced by a blood pressure cuff inflated to 200 millimeters of mercury (mmHg) or at least 15mmHg higher than the systolic pressure if systolic > 185mmHg or until the radial pulse is obliterated. This can occur during anesthesia induction and incision/dissection prior to manipulation or clamping of the carotid.

Those randomized to RIPC will undergo a standard protocol of 4 cycles of 5 minutes of forearm ischemia with 5 minutes of reperfusion requiring 35 minutes for an application. Forearm ischemia will be induced by a blood pressure cuff inflated to 200mmHg or at least 15mmHg higher than the systolic pressure if systolic > 185mmHg or until the radial pulse is obliterated. This can occur during anesthesia induction and incision/dissection prior to manipulation or clamping of the carotid.

Inclusion Criteria: Patients undergoing carotid endarterectomy Indication for surgery must be symptomatic disease with >50% stenosis by duplex ultrasound or asymptomatic disease with >60% stenosis by duplex ultrasound Exclusion Criteria: Lack of radial pulse on either arm Known Deep venous thrombosis (DVT) in arm Arteriovenous fistula or graft in both arms Diagnosed hypercoagulable state Pre-existing lymphedema or axillary node dissection both arms Diagnosis of dementia, intellectual disability, or mental illness including depression, anxiety, or schizophrenia Simultaneous coronary artery bypass grafting

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