In the last decade, insulin has gained increased attention and importance in the management of a spectrum of critical illnesses including sepsis, heart failure, and cardiac drug toxicity. The benefits of insulin go well beyond simple control of hyperglycemia. In xenobiotic-induced myocardial depression the use of high-dose insulin along with sufficient glucose to maintain euglycemia can restore normal hemodynamics.
To understand the role of insulin specifically for resuscitating cardiac drug toxicity, it is useful to briefly review the altered myocardial physiology that occurs during drug-induced shock.
The hallmark of severe beta-adrenergic antagonist (BAA) and calcium channel blocker (CCB) toxicity is cardiogenic shock with bradycardia, vasodilation, and decreased contractility.7 This is due to direct β-adrenergic receptor antagonism and calcium channel blockade. In addition to direct receptor or ion channel effects, metabolic derangements may occur that closely resemble diabetes with acidemia, hyperglycemia, and insulin deficiency.
In the nonstressed state, the heart primarily catabolizes free fatty acids for its energy needs. On the other hand, the stressed myocardium switches preference for energy substrates to carbohydrates, as demonstrated in models of both BAA and CCB toxicity.19,35 The greater the degree of shock, the greater the demand for carbohydrates.20 The liver responds to stress by making more glucose available via glycogenolysis. As a result, blood glucose concentrations are elevated. Hyperglycemia is noted both in animal models and in human cases of cardiac drug overdose.4,9,22,36 Hyperglycemia is especially evident with CCB toxicity. This is because CCBs interfere with carbohydrate use by inhibiting pancreatic insulin release that is necessary to transport glucose across cell membranes. Insulin release from the islet cell requires functioning L-type or voltage-gated calcium channels similar to those found in myocardial and vascular tissue. Calcium channel blocking drugs directly inhibit pancreatic calcium channels.6 In models of verapamil toxicity, circulating glucose increases without an associated increase in insulin.20 There is additional evidence that CCBs interfere with phosphotidyl inositol 3-kinase—mediated glucose transport into cells.1 As a result of diminished circulating insulin and inhibited enzymatic glucose uptake, glucose movement into cells becomes concentration dependent and may not sufficiently support the myocardial demand. Calcium channel blockers further contribute to metabolic abnormalities by inhibiting lactate oxidation.19,23 This likely occurs through inhibition of pyruvate dehydrogenase, the enzyme responsible for conversion of pyruvate to acetylcoenzyme A (acetyl-CoA). As a result, pyruvate is preferentially converted to lactate, rather than the acetyl-CoA that would ordinarily enter the Krebs cycle; lactate then accumulates. Lactate accumulation and acidemia are consistent manifestations of CCB toxicity.7,23
Initially, insulin's ability to improve cardiac function was attributed to increased catecholamine release. However, there is evidence that this is not the mechanism. For example, β-receptor antagonism does not inhibit improved myocardial performance that followed insulin administration.24,35 In a CCB toxic model that measured circulating hormone concentrations, insulin therapy improved function and survival without increasing catecholamines.22 In ...