title: Impact of remote ischemic preconditioning preceding coronary artery bypass grafting on inducing neuroprotection (RIPCAGE): study protocol for a randomized controlled trial.
abstract: BACKGROUND
  Neurological complications after cardiac surgery have a profound impact on postoperative survival and quality of life. The increasing importance of strategies designed to improve neurological outcomes mirrors the growing risk burden of the contemporary cardiac surgical population. Remote ischemic preconditioning (RIPC) reduces adverse sequelae of ischemia in vulnerable organs by subjecting tissues with high ischemic tolerance to brief periods of hypoperfusion. This trial will evaluate the neuroprotective effect of RIPC in the cardiac surgical arena, by employing magnetic resonance imaging (MRI) and neurocognitive testing.
  
  
  METHODS
  Patients scheduled for elective coronary artery bypass grafting with the use of cardiopulmonary bypass will be screened for the study. Eligible patients will be randomized to undergo either a validated RIPC protocol or a sham procedure. The RIPC will be induced by inflation of a blood pressure cuff to 200 mmHg for 5 minutes, followed by a 5-minute reperfusion period. Three sequences of interchanging cuff inflations and deflations will be employed. Neurocognitive testing and MRI imaging will be performed preoperatively and on postoperative day 7. Paired pre- and postoperative neurocognitive and neuroimaging data will then be compared. The primary composite outcome measure will consist of new ischemic lesions on brain MRI, postprocedural impairment in brain connectivity on resting-state functional MRI (rs-fMRI), and significant new declines in neurocognitive performance. The secondary endpoint measures will be the individual components of the primary endpoint measures, expressed as continuous variables, troponin T release on postoperative day 1 and the incidence of major adverse cardiovascular events at 3 months postoperatively. Major adverse cardiovascular events, including accumulating cardiovascular mortality, stroke, nonfatal myocardial infarction, and rehospitalization for ischemia, will form a composite endpoint measure.
  
  
  CONCLUSIONS
  This trial will aim to assess whether RIPC in patients subjected to surgical myocardial revascularization employing cardiopulmonary bypass initiates a neuroprotective response. Should the results of this trial indicate that RIPC is effective in reducing the incidence of adverse neurological events in patients undergoing coronary artery bypass grafting, it could impact on the current standard of care.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT02177981.
authors.affiliation: Department of Cardiac Surgery, University Hospital Center Zagreb, University of Zagreb, Kispaticeva 12, 10 000 Zagreb, Croatia. hgasparovic@gmail.com.
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Gasparovic
authors.forename: Tomislav
authors.initials: T
authors.lastname: Kopjar
authors.forename: Milan
authors.initials: M
authors.lastname: Rados
authors.forename: Alan
authors.initials: A
authors.lastname: Anticevic
authors.forename: Marko
authors.initials: M
authors.lastname: Rados
authors.forename: Branko
authors.initials: B
authors.lastname: Malojcic
authors.forename: Visnja
authors.initials: V
authors.lastname: Ivancan
authors.forename: Tea
authors.initials: T
authors.lastname: Fabijanic
authors.forename: Maja
authors.initials: M
authors.lastname: Cikes
authors.forename: Davor
authors.initials: D
authors.lastname: Milicic
authors.forename: Vladimir
authors.initials: V
authors.lastname: Gasparovic
authors.forename: Bojan
authors.initials: B
authors.lastname: Biocina
mesh_terms: D002315:Cardiopulmonary Bypass / Q000009:adverse effects; D002560:Cerebrovascular Circulation; D002561:Cerebrovascular Disorders / Q000175:diagnosis / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D002985:Clinical Protocols; D001026:Coronary Artery Bypass / Q000009:adverse effects*; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000503:physiopathology / Q000601:surgery*; D017523:Croatia; D004311:Double-Blind Method; D017558:Elective Surgical Procedures; D006801:Humans; D019194:Ischemic Preconditioning / Q000009:adverse effects / Q000379:methods*; D008279:Magnetic Resonance Imaging; D009483:Neuropsychological Tests; D011446:Prospective Studies; D012039:Regional Blood Flow; D012107:Research Design; D013997:Time Factors; D016896:Treatment Outcome; D034941:Upper Extremity / Q000098:blood supply*