Remote Ischemic Preconditioning for Carotid Endarterectomy
Condition: Carotid Stenosis; Endarterectomy, Carotid
MeSH terms: Carotid Stenosis
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Remote Ischemic Preconditioning
Intervention type(s): Procedure
Intervention description(s): 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.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Prevention