Propofol Cardioprotection for Type II Diabetics
Condition: Myocardial Injury
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      The purpose of this study is to determine if an intravenous anesthetic with antioxidant
      properties will protect the heart of diabetic patients from injury while undergoing coronary
      bypass surgery.
    

Detailed description: 
      Diabetic patients are at elevated risk for low cardiac output syndrome. This high risk
      scenario adversely affects up to 26% of patients recovering from cardiac surgery. Aggressive
      hemodynamic treatments are required, but can prove inadequate. Low cardiac output syndrome
      can quadruple the overall mortality rate for aortocoronary bypass surgery from 2% to 8%.
      Therefore, an urgent need exists for effective forms of preemptive cardioprotection and
      antioxidant protection may play a crucial role. Our research into the therapeutic potential
      of propofol, an intravenous anesthetic with antioxidant properties, could have significant
      impact on outcome in this select population. The proposed study represents a novel
      therapeutic approach for the prevention of myocardial ischemia-reperfusion injury in diabetic
      patients undergoing cardiac surgery with cardiopulmonary bypass.

      RESEARCH PLAN

      Two blinded, randomized controlled phase II studies will be conducted in patients undergoing
      primary aortocoronary bypass surgery.

      STUDY A

      Specific Aims:

        1. To determine whether propofol increases nitric oxide bioavailability and decreases ET-1
           formation in diabetic patients undergoing aortocoronary bypass surgery

        2. To determine whether propofol inhibits superoxide formation or downregulates iNOS gene
           expression in cardiac tissue.

      Hypothesis:

      Oxidant stress during myocardial reperfusion promotes the conversion of NO to the cardiotoxic
      free radical, peroxynitrite, and enhances the formation of the vasoconstrictor ET-1 in
      diabetic patients. We postulate that these factors cause postoperative cardiac dysfunction of
      the ischemic-reperfused diabetic heart.

      STUDY B

      Specific Aim:

      To determine whether a high dose of intravenous insulin increases the effect of propofol on
      perioperative oxidative stress.

      Hypothesis: Insulin, by preventing hyperglycemia, enhances propofol's effect on oxidative
      stress.

      Methods

      In Study A, 144 patients (72 patients with Type II DM + 72 patients with no DM) will be
      randomized to receive either propofol 120 ug/kg/min or isoflurane 0.5 to 2% for a treatment
      interval of 120 to 150 min (10 min before and during CPB, and for 15 min following aortic
      declamping). All patients will receive a continuous intravenous (I.V.) infusion of insulin as
      needed to maintain glucose levels at 8 to 12 mmol/L.

      In Study B, 72 Type II diabetic patients will be randomized to isoflurane or propofol
      cardioprotection. All patients will be treated with the perioperative hyperinsulinemic clamp
      to maintain blood glucose levels within a target range of 4.5 - 6 mmol/L for up to 6 hours
      following release of aortic crossclamp.

      Arterial and coronary sinus blood will be sampled simultaneously before initiation of CPB and
      at 5 min reperfusion for Troponin I, 15-F2t-isoP, nitrotyrosine and tyrosine, ET-1, and
      TNF-alpha. An index of myocardial derived 15-F2t-isoP and peroxynitrite will be determined
      from the Cs-Ao difference in percentage ratio of plasma free 15-F2t-isoP and nitrotyrosine to
      tyrosine, respectively.

      Atrial tissue will be sampled before initiation of CPB and at 15min reperfusion for detection
      of iNOS, eNOS and superoxide formation. This will coincide with central venous blood sampling
      for measurement of the concentration of propofol.

      The levels of 15-F2t-isoP, nitrotyrosine and tyrosine, ET-1, and TNF-alpha in blood will be
      determined at 2 hours postoperatively. Troponin I levels will be determined at 2, 12, and 24
      hours postoperatively. Cardiac function will be assessed up to 6 hours postoperatively by
      pulmonary artery catheter and transesophageal echocardiography.

      This study represents a novel therapeutic approach for the prevention of myocardial
      ischemia-reperfusion injury. This study on diabetic patients will provide the prerequisite
      knowledge for a randomized clinical trial powered to detect clinical outcomes in this high
      risk patient population.
    

Intervention name(s): Propofol; Propofol
Intervention type(s): Drug; Drug
Intervention description(s): Propofol cardioprotection : Ten minutes prior to initiation of CPB, we will stop delivery of isoflurane, inject 1 mg/kg iv and then continuously infuse propofol at 120µg/kg/min IV until 15 min after release of the aortic cross clamp (reperfusion).; Volatile Anesthetic preconditioning : Anesthesia will be maintained using an inspired concentration of isoflurane between 0.5-2% before, during, and after CPB, without administration of propofol. For ten minutes prior to the initiation of CPB we will deliver Isoflurane 2.5% end tidal then resume maintenance anesthesia as described.
Intervention MeSH terms: Propofol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: coronary artery bypass surgery; coronary artery bypass grafting; cardiopulmonary bypass; diabetes; myocardial injury markers,; sex differences; cardiac anesthesia; inhalational anesthetics