The insulin cardioplegia trial.

See related article on page 928. I n 1965 Sodi-Pollares and colleagues1 first used glucose-insulin-potassium (GIK) solutions to treat patients with acute myocardial infarctions and found that this limited infarct size, reduced ventricular ectopy, and improved survival. Early studies in isolated heart preparations with regional ischemia showed that GIK decreased infarct size, increased high-energy phosphate levels, and improved ventricular function.2 Clinical studies in patients with acute myocardial infarction demonstrated that GIK enhanced myocardial performance.3 However, enthusiasm for GIK was dampened by a British Medical Research Council clinical trial of patients with acute myocardial infarction that failed to show any survival benefit with GIK therapy.4 In that study, GIK protocols were inconsistent, such that different doses and volumes of GIK were administered at various times from the onset of the infarct, making it difficult to determine the effectiveness of GIK therapy. The role of glucose and insulin in cardiac surgery was further diminished by the introduction of cold chemical cardioplegia and hypothermic cardiopulmonary bypass because of the inhibitory effects of hypothermia on glucose and insulin metabolism. However, the increased numbers of patients requiring urgent coronary artery bypass grafting (CABG) for acute coronary syndromes, many with reduced ventricular function, and the introduction of warm cardioplegia and cardiopulmonary bypass techniques have prompted a renewed interest in substrate enhancement with glucose and insulin in an attempt to augment myocardial protection and improve clinical outcomes for these high-risk patients. There are several mechanisms by which glucose and insulin protect the ischemic myocardium. Although the primary energy source for the nonischemic myocardium is free fatty acids, glucose is the preferred substrate during periods of ischemia. Adenosine triphosphate derived from glycolysis is vital for stabilization of membrane ion transport, which in turn is crucial to the cellular integrity of myocytes, endothelium, and vascular smooth muscle cells. Preservation of coronary endothelial function during cardioplegic arrest has been shown to decrease ischemic necrosis.5 Glucose also esterifies intracellular free fatty acids, which decreases their toxic end-products, oxygen free radicals. Because glucose is a direct precursor of pyruvate, which is carboxylated to the citric acid cycle substrates malate and oxaloacetate, it can replenish depleted postischemic substrates, thus stimulating oxidative metabolism. Experimental studies have shown that glucose converted to pyruvate can restore contractile function through the replenishment of depleted citric acid substrates.6 Insulin benefits the postischemic myocardium by stimulating pyruvate dehydrogenase activity, which stimulates aerobic metabolism on reperfusion. Exogenous insulin helps to reverse insulin resistance during cardiopulmonary bypass, which contributes to increased serum concentrations of free fatty acids and decreased myocardial uptake of glucose. Intravenous infusions of insulin after CABG have been shown to decrease the levels of free fatty acids and increase myocardial uptake of glucose.7 Insulin added to antegrade and retrograde tepid (29°C) blood cardioplegia has been shown to stimulate aerobic metabolism during reperfusion, preventing lactate release and improving left ventricular stroke work index.8 Insulin is especially beneficial for patients with diabetes and acute coronary ischemia. Patients with diabetes are characterized by impaired glucose uptake and increased plasma levels of free fatty acids during ischemia, which leads to arrhythmias and depressed myocardial performance. Insulin enhances myocardial glucose utilization and deFrom the Department of Cardiothoracic Surgery, Boston Medical Center, Boston, Mass.