Hypoglycemia Tied to Cardiac Arrhythmias

Lethal cardiac arrhythmias triggered by hypoglycemia are likely behind sudden death often seen in patients with type 1 diabetes, researchers found.

In a series of experiments in rats, increasing hypoglycemia severity led to arrhythmias that ultimately killed the animals, including higher-grade second-degree heart block and third-degree heart block, according to Simon Fisher, PhD, of Washington University of St. Louis, and colleagues.

But they also saw that an intracerebroventricular infusion of glucose reduced mortality due to severe hypoglycemia from 86% to 33% (P<0.05), and giving certain adrenergic receptor blockers completely prevented death during hypoglycemia (P<0.029), they reported online in Diabetes.

"It is shown for the first time that fatal cardiac arrhythmias occur during severe hypoglycemia and can be reduced by intracerebroventricular glucose infusion and prevented by beta-adrenergic blockade, indicating that brain neuroglycopenia and the striking sympathoadrenal response mediate fatal cardiac arrhythmias during severe hypoglycemia," they wrote.

Researchers have been trying to understand the mechanisms by which the risk of sudden death is increased in patients with type 1 diabetes. Some have hypothesized that such deaths are linked to excess insulin administration resulting in severe hypoglycemia.

Higher insulin levels could diminish potassium levels while simultaneously raising catecholamine levels, potentially contributing to arrhythmias, the researchers said. Thus, preventing hypokalemia or blocking the action of catecholamines may also protect against arrhythmias and cardiorespiratory arrest during severe hypoglycemia.

To test those hypotheses, Fisher and colleagues conducted a series of experiments in which they induced severe hypoglycemia in Sprague-Dawley rats.

In the first experiment, they found that death due to severe hypoglycemia was worse among rats with diabetes: mortality was 21% in nondiabetic rats compared with 36% in diabetic rats (P<0.05).

However, rats that had previously been exposed to recurrent, moderate hypoglycemia had markedly less mortality during severe hypoglycemia (P<0.05), though the reason for this remained unclear, the researchers said.

In the next study, Fisher and colleagues gave both diabetic and nondiabetic animals potassium supplements during hypoglycemia. This tended to reduce mortality associated with severe hypoglycemia, but the finding didn't achieve significance (P<0.08).

In the third experiment in the series, the team induced severe hypoglycemia in six nondiabetic rats that were monitored via an electrocardiogram (ECG). These rats had a lengthened corrected QT interval compared with baseline (172 ms versus 122 ms), translating to a 40% increased ventricular depolarization and repolarization phase (P<0.001).

Arrhythmias didn't occur during moderate hypoglycemia, but after the onset of severe hypoglycemia, the researchers saw premature ventricular contractions (PVCs) and narrow complex second-degree heart block. And as the rats lingered in severe hypoglycemia, the arrhythmias became more intense, with more frequent and higher-grade second-degree heart block, followed by third-degree heart block, both of which typically preceded death.

In the final two experiments, Fisher and colleagues assessed whether intracerebroventricular glucose infusion and adrenergic blockade had an effect on hypoglycemia-induced mortality.

They found that infusing glucose into the third ventricle of the brain during severe hypoglycemia significantly reduced mortality due to severe hypoglycemia from 86% to 33% (P<0.05).

A quarter of the rats given intracerebroventricular glucose infusion didn't have any subsequent arrhythmias, and the incidence of third-degree heart block was significantly diminished in these animals (P<0.05).

Adrenergic blockade was even more effective, with combined alpha/beta blockade or beta blockade alone completely preventing death in all hypoglycemic animals, compared with a mortality rate of 33% among rats that weren't given these drugs (P<0.029).

Alpha blockade alone, however, had no effect on mortality, they noted.

Alpha/beta and beta blockade alone also reduced the frequency of arrhythmias compared with controls (P<0.001).

Fisher and colleagues concluded that their findings suggest death due to severe hypoglycemia is "mediated by brain neuroglycopenia and the sympathoadrenal response that leads to fatal cardiac arrhythmias."

"Implications of the current studies could lead to improvement in treatment strategies that aim to reduce the mortality of individuals at risk or insulin-induced hypoglycemia," they wrote.

Source: www.medpagetoday.com