Clinical and genomic responses to remote ischemic preconditioning

Hospital For Sick Chldrn (Toronto), Toronto ON

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): The use of cardiopulmonary bypass for cardiac surgery in children results in important morbidity and sometimes mortality related to the adverse effects of bypass induced by hypothermia, hemolysis, acid-base management, hemodilution and hypoxia-ischemia. After bypass, reperfusion occurs and induces ischemia reperfusion injury. Inflammation and oxidative stress are key mediators in this process. The objective of this study is to determine if application of a stimulus of remote ischemic preconditioning (RIPC) prevents or lessens the multi-organ dysfunction related to ischemia-reperfusion injury in children undergoing open heart surgery with cardiopulmonary bypass. We will also seek to determine mechanistic gene expression profiles associated with this treatment effect, and baseline profiles that are predictive of clinical outcomes after surgery. We propose a randomized, double-blind sham-controlled clinical trial. At the time preparation for surgery, 4 cycles of 5 minutes each of lower limb ischemia will be induced by inflation of a blood pressure cuff. Gene expression profiling will be noted at induction of anesthesia before application of the RIPC stimulus, 15 minutes after RIPC and at 24 after cessation of cardiopulmonary bypass. The primary outcome will be total duration of post-operative hospital stay, and 1200 patients will be studied, with a hypothesized decrease of 1 day associated with RIPC. Additional outcomes will reflect multi-organ dysfunction and inflammation and their impact, and include duration of mechanical ventilation, duration of stay in the intensive care unit, and physiologic measures over the first 48 hours after surgery. These measures will include indices of renal (urine output, urea, creatinine), cardiac (troponin I, inotrope score), pulmonary (pulmonary and airway mechanics, ventilation parameters), hematologic (blood counts), hepatic (transaminases, INR), metabolic (lactate, arterial and mixed venous oxygen saturations) dysfunction and inflammatory markers (cytokines, CRP). The impact of RIPC on these outcomes will be compared, and related to gene expression patterns, particularly those involved in the inflammatory cascade. Our study will have an important impact on improving the recovery and reducing complications for children undergoing open heart surgery. It will also define important ways in which the body can be further protected from the stresses of undergoing surgery using heart-lung bypass. (End of Abstract)