Coronary bypass surgery: protective effects of insulin or of prevention of hyperglycemia, or both?

One of the major risks of coronary bypass surgery is the impact of transient ischemia-reperfusion of the myocardium inherent to the surgical technique, with or without the use of extracorporeal circulation. The ensuing reversible postoperative myocardial dysfunction, referred to as myocardial “stunning,” can have severe consequences because low cardiac output can evoke failure of other vital organs. Myocardial dysfunction necessitates pharmacological and/or mechanical support of the heart and prolongs the time in intensive care and the hospital. A metabolic strategy to protect the myocardium from the deleterious effects of ischemia and reperfusion that was suggested almost five decades ago by Dr. Sodi-Pallares is the infusion of glucose, insulin, and potassium (GIK) (1). The rationale behind this intervention was to provide the heart with an alternative metabolic substrate that requires less oxygen and to prevent arrhythmia in ischemic hearts. Indeed, the metabolic cocktail of GIK could fuel the heart with an energy-saving substrate while increasing myocardial oxygen efficiency. Shifting substrate utilization in the ischemic myocardium from predominantly free fatty acids to anaerobic glycolysis reduces oxygen consumption and can thereby protect the vulnerable (post)ischemic cardiomyocytes by optimizing the balance between oxygen supply and consumption. Increasing potassium flux into the cardiomyocytes could also reduce the risk of malignant arrhythmias. In addition to these metabolic effects of GIK, it was later shown that insulin is also a direct actor in the GIK cocktail. Via binding to the insulin receptor on cardiomyocytes and by triggering the insulin signaling cascade, intracellular survival pathways are activated that could mediate cardioprotection (2) and, in the ischemic myocardium, reduce the generation and accumulation of toxic free radicals. However, despite many studies in different experimental settings of myocardial ischemia and reperfusion, and despite valid insights into the underlying mechanisms, the definite role of GIK in clinical practice remains controversial even today, half a century after the introduction of the GIK concept by Sodi-Pallares (1, 3–5). Large clinical studies produced opposing outcomes, possibly due to variable study design and composition of GIK. Particularly GIK in high doses appeared to generate positive outcomes in randomized placebo-controlled studies of patients with acute myocardial infarction (4). But the more recent large trials (6, 7) did not confirm such a benefit of GIK therapy on cardiac mortality and morbidity. Since 2001, however, the focus of metabolic research in acute medicine shifted to the potential deleterious effects of hyperglycemia in stressed cells (8) and thereby reopened the field. The renewed interest was generated by our study of patients with critical illness treated in tertiary referral surgical intensive care (9). Sixty percent of these patients had been admitted to intensive care after complex or complicated cardiac surgery with high euroscores (9, 10). The study showed that titrating insulin infusion to prevent blood glucose exceeding the upper normal limit after the surgery and continuing during the entire stay in an intensive care unit substantially reduced morbidity and mortality, a benefit that was maintained at least up to 4 yr after surgery (10). A subsequent study confirmed the acute morbidity benefits in adult medical intensive care unit patients (11), and another extended the morbidity and mortality benefits to critically ill infants and children (12). Implementation studies also reported similar benefits (13, 14). In-depth analyses of the results suggested that the prevention of hyperglycemia, not the infusion of insulin per se, explained most of these benefits (15, 16). Studies in animal models of critical illness further unraveled this important