Dariusz Szurlej

Diazoxide protects myocardial mitochondria, metabolism, and function during cardiac surgery: A double-blind randomized feasibility study of diazoxide-supplemented cardioplegia

OBJECTIVES The study was designed to assess whether diazoxide-mediated cardioprotection might be used in human subjects during cardiac surgery. METHODS Forty patients undergoing coronary artery bypass grafting were randomized to receive intermittent warm blood antegrade cardioplegia supplemented with either diazoxide (100 micromol/L) or placebo (n = 20 in each group). Mitochondria were assessed before and after ischemia and reperfusion in myocardial biopsy specimens. Myocardial oxygen and glucose and lactic acid extraction ratios were measured before ischemia and in the first 20 minutes of reperfusion. Hemodynamic data were collected, and troponin I, creatine kinase-MB, and N-terminal prohormone brain natriuretic peptide levels were measured. All outcomes were analyzed by using mixed-effects modeling for repeated measures. RESULTS No deaths, strokes, or infarcts were observed. Patients received, on average, 36.2 +/- 1.2 mg of diazoxide and 37.3 +/- 1.9 mg of placebo (P = .6). Diazoxide added to cardioplegia prevented mitochondrial swelling (8899 +/- 474 vs 9273 +/- 688 pixels before and after the procedure, respectively; P = .6) compared with that seen in the placebo group (8474 +/- 163 vs 11,357 +/- 759 pixels, P = .004). No oxygen debt was observed in the diazoxide group. Glucose consumption and lactic acid production returned to preischemic values faster in the diazoxide group. The following hemodynamic parameters differed between the diazoxide and placebo groups, respectively, in the postoperative period: cardiac index, 3.0 +/- 0.09 versus 2.6 +/- 0.09 L . min(-1) . m(-2) (P = .002); left cardiac work index, 2.81 +/- 0.07 versus 2.31 +/- 0.07 kg/m(2) (P < .001); oxygen delivery index, 420 +/- 14 versus 377 +/- 13 mL . min(-1) . m(-2) (P = .03); and oxygen extraction ratio, 29.3% +/- 1.1% versus 32.6% +/- 1.1% (P = .02). Postoperative myocardial enzyme levels did not differ, but N-terminal prohormone brain natriuretic peptide levels were lower in the diazoxide group (120 +/- 27 vs 192 +/- 29 pg/mL, P = .04). CONCLUSIONS Supplementing blood cardioplegia with diazoxide is safe and improves myocardial protection during cardiac surgery, possibly through its influence on the mitochondria.

Rationale for Propofol Use in Cardiac Surgery

p ROPOFOL IS A COMMONLY USED intravenous anesthetic agent. Chemically, propofol is a lipophilic, sterically indered alkylated phenol that is a very weak acid.1,2 Pharmaokinetic and pharmacodynamic properties make propofol a seful drug in everyday anesthesia with rapid and clear emerence, precise control of the level of sedation, and lack of umulative effects even after prolonged administration.1-4 Alhough the terminal half-life of propofol is long, recovery is apid because of the slow mobilization from the highly liophilic tissue compartment.1-4 The indications for propofol use include the induction and aintenance of anesthesia for most surgical procedures, and it an be extended into the postoperative setting or intensive care nit for sedation. Rapid redistribution and elimination make ropofol valuable for short procedures and ambulatory surery.1-4 Moreover, the agent possesses antiemetic, antipruritic, nd anticonvulsant properties.1-4 Propofol is also widely used in subjects with cardiac disase.3,4 An anesthetic drug for cardiac surgery should provide ntraoperative amnesia, analgesia, and hemodynamic stability ith minimal direct myocardial depression and rapid recovery; deally, with weak inotropic support.4 Pharmacokinetic proprties of propofol favor its use in clinical practice in cardiac urgery patients.3-5 The induction of anesthesia with an opioidenzodiazepine/etomidate combination followed by a mainteance infusion of propofol supplemented with an inhalation gent or opioid analgesic or both as needed are considered cceptable for patients undergoing routine cardiac surgery.3 part from general anesthesia, major indications for propofol se are sedation during painful procedures (eg, cardioversion), ternal wound debridement, central venous catheter insertion, nd transesophageal echocardiography (Table 1).3,4 Propofol is safely administered to patients with cirrhosis and enal failure, with no impairment in its clearance.1 However, in omparison with other agents, the induction dose of propofol as a relatively higher prevalence of respiratory depression, hort-lived apnea, and arterial blood pressure (estimated even at