Impact of Remote Ischemic Preconditioning Preceding Coronary Artery Bypass Grafting on Inducing nEuroprotection
Condition: Brain Ischemia; Postoperative Confusion
MeSH terms: Brain Ischemia; Confusion; Ischemia
Study type: Interventional

Summary: 
      Coronary artery disease (CAD) is the leading cause of death worldwide. Patients with severe
      CAD are often treated with coronary artery bypass grafting (CABG). Novel treatment strategies
      need to be pursued to respond to the continuous increase in the risk profile of contemporary
      CABG patients. Surgical myocardial revascularization is commonly performed with the use of
      cardiopulmonary bypass (CPB). Neurological impairment following CABG may take on the form of
      a new-onset motor deficit or postoperative cognitive dysfunction. The former is rare, but
      potentially devastating. Conversely, declines in attention, memory and fine motor skills can
      frequently be documented.

      Ischemic preconditioning is a phenomenon of an endogenous protective response to organ
      ischemia, which is triggered by brief cycles of nonlethal ischemia and reperfusion in tissues
      known to be more resistant to ischemic insults. In clinical practice remote ischemic
      preconditioning (RIPC) is achieved by inflicting short periods of ischemia with intermittent
      restitution of flow to the upper extremity. This intervention has been shown to be effective
      in the reduction of myocardial injury in cardiac surgical patients. The hypothesis tested in
      this research proposal is that RIPC will decrease the extent of postoperative neurological
      injury following CABG.

      In this research project, 70 patients scheduled for an elective CABG will be recruited at a
      single center. They will be randomly allocated to either undergo RIPC (intervention arm) or a
      sham procedure (control arm). Inflating a blood pressure cuff to 200 mmHg for 5 min will
      induce RIPC, thereby inducing a brief period of ischemia. This will be followed by a 5-minute
      arm reperfusion. In total, three cycles of arm ischemia and reperfusion will be induced in
      this fashion.

      All patients will undergo pre- and post-procedural magnetic resonance imaging (MRI) of the
      brain, as well as neurocognitive testing. The array of MRI tools that will be used for the
      quantification of brain injury will include fluid attenuated inversion recovery, diffusion
      weighted and susceptibility weighted imaging, coupled with resting state functional MRI.

      The investigators aim to determine whether RIPC can reduce the adverse impact of CPB on
      neurological outcome as evaluated by MRI detectable brain ischemia and neurocognition.
    

Detailed description: 
      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:

        1. Brain connectivity profiles on resting-state functional MRI (rs-fMRI).

        2. Pooled ischemic volumes of new diffusion-weighted imaging (DWI) hyperintensity.

        3. 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.
    

Intervention name(s): Remote ischemic preconditioning; Control
Intervention type(s): Procedure; Procedure
Intervention description(s): A blood pressure cuff will be placed on the left arm and three cycles of 5 min ischemia followed by 5 min reperfusion will be applied.; The cuff will be placed around the arm but not inflated.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Remote Ischemic Preconditioning; Coronary Artery Bypass Grafting; Diffusion Weighted Magnetic Resonance Imaging; Resting State Functional Magnetic Resonance Imaging; Postoperative Cognitive Dysfunction