Remote Ischemic Preconditioning for Carotid Endarterectomy

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.

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