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A clinical appraisal of propofol-mediated, antioxidant-based cardioprotection during coronary artery bypass grafting with cardiopulmonary bypass

University of British Columbia

Coronary artery disease is the leading cause of death in North America. The invasiveness of its treatment depends on its severity; less severe disease can be treated pharmacologically or surgically without significantly different outcomes, but coronary artery bypass grafting (CABG) clearly reduces mortality among medium- and high-risk patients compared to percutaneous and non-surgical intervention. Although the majority of patients undergoing surgical revascularization emerge without severe postoperative complications, a significant portion of patients encounter a postoperative complication known as low cardiac output syndrome which can quadruple the overall mortality rate for CABG. Intraoperative ischemia reperfusion injury is a major factor in the development of low cardiac output syndrome; so effective intraoperative myocardial protection is central to reducing its incidence, and represents an opportunity to considerably improve patient outcomes. The introductory chapter of this thesis describes the origin and role of reactive oxygen species (ROS) in myocardial ischemia-reperfusion injury. In addition, it introduces key strategies targeted to reduce ROS-mediated myocardial ischemia-reperfusion injury, highlighting key clinical studies that translated these strategies to reduce the severity of ischemia-reperfusion injury during CABG. The central hypothesis of the clinical project on which this thesis is based states that propofol reduces the incidence of low cardiac output syndrome subsequent to CABG with CPB by decreasing the magnitude of 15-F₂t-isoprostane generation during ischemia-reperfusion. The second chapter introduces propofol, and will review previous studies that explore its cardioprotective potential. The experimental section of this thesis describes the development of a quantitative technique for propofol analysis in whole blood, and its application in a dose finding study that define the parameters for achieving experimentally relevant concentrations of propofol during cardiopulmonary bypass. These two studies were fundamental to the development of a clinical study evaluating ROS generation and the incidence low cardiac output syndrome in patients undergoing CABG surgery. Preliminary results that address the central hypothesis are subsequently presented, along with an alternative proposed mechanism for propofol-mediated cardioprotection. This thesis will conclude with a summary of findings and a description of several future studies aimed at testing, generating, and evaluating new hypotheses.

Text

2011-04-18

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/33736

Pharmacology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/