Calcium and Digoxin vs Calcium Alone for Severe Verapamil Toxicity

Abstract

Abstract. Calcium chloride (CaCl 2 ) is ineffective in severe calcium channel antagonist overdoses. Digoxin increases intracellular calcium by inhibiting the sodium-potassium adenosine triphosphatase enzymes. Objective: To examine the effect of calcium and digoxin on the treatment of verapamil toxicity. Methods: Sixteen dogs were instrumented to monitor hemodynamics. Verapamil toxicity (50% decrease in mean arterial pressure) was induced with verapamil (VER) at 6 mg/kg/hr and maintained for 30 minutes by titrating the VER rate. Following toxicity, the dogs received either digoxin (0.018 mg/kg) (DIG) (n = 8) or saline (No-DIG) (n = 8). Both groups received VER at three sequential rates (1 mg/kg/hr from 0 to 90 min, 6 mg/kg/hr from 90 to 130 min, and 18 mg/kg/hr from 130 to 170 min). Calcium boluses were given (500 mg at 0 and 15 min; 1 g at 140, 150, and 160 min). Data were analyzed using a repeated-measures analysis of covariance comparing DIG vs No-DIG across the infusion rates and time. Animal weight, dose of VER administered during the toxicity phase, and baseline values were included as covariates. Mortality rates were compared at 230 minutes following a total dose of 500 mg of VER. Results: The DIG group had a higher systolic blood pressure (SBP) than the No-DIG group during the 1-mg/kg/hr (early p = 0.028, late p = 0.01), 6-mg/kg/hr (p = 0.051), and 18-mg/kg/hr (p = 0.038) VER 1 This is because the overdoses of the sustained-release preparation, which contains large doses of the drug, result in profound toxicity over an extended period of time. Toxicity develops when intracellular calcium is decreased in cardiac and vascular smooth muscle, which is why intravenous (IV) calcium chloride (CaCl 2 ) is used as one of the initial therapies. In large-dose calcium channel antagonist overdoses, calcium is usually ineffective, and other therapies such as atropine, glucagon, cardiac pacing, vasopressors, 2 Even with these therapies, fatalities occur.In the presence of calcium channel antagonist toxicity, IV calcium increases intracellular calcium by creating a large extracellular-to-intracellular concentration gradient and forcing calcium through unblocked calcium channels.2 In large overdoses, calcium is ineffective because few if any channels are unblocked and calcium is unable to enter the cell.Digoxin increases intracellular calcium by initially inhibiting the sodium-potassium adenosine triphosphatase (Na-K ATPase) pump. This inhibition results in an increased intracellular sodium, which is then exchanged for calcium by an exchange mechanism that is not blocked by the calcium channel antagonist. Since calcium has limited effect in large calcium channel antagonist overdoses, the addition of digoxin may facilitate the movement of calcium intracellularly by passing the blocked calcium channels. Our hypothesis was that calcium plus a high therapeutic dose of digoxin would be more effective than calcium alone in reversing the hemodynamic effects of verapamil in an animal model of severe verapamil toxicity.

The Effects of Intravenous Calcium in Patients with Digoxin Toxicity

“…Digoxin, like other cardiac glycosides, inhibits the sodium-potassium ATPase pump, thereby increasing the intracellular sodium concentration (1)(2)(3)(4)(5). The increased intracellular sodium inhibits sodium-dependent calcium transport out of the cytoplasm, resulting in increased intracellular calcium, and thus increased inotropy.…”

Dose-dependent Hemodynamic Effect of Digoxin Therapy in Severe Verapamil Toxicity

“…13 We previously demonstrated that a high therapeutic dose of digoxin (0.018 mg/kg, or two times the loading dose of digoxin) plus calcium (200 mg/kg) increased systolic blood pressure by 15% to 21% versus calcium alone in a model of severe verapamil toxicity (25 mg/kg over 4 hours). 3 Additionally, neither ventricular tachycardia nor ventricular fibrillation occurred in the digoxin group. A similar result was found in a model of mild-to-moderate verapamil toxicity (4 mg/kg over 30 minutes) treated with calcium (7.5 mg/kg) plus digoxin (0.009 mg/kg).…”

“…5 The verapamil infusion rate and titration period previously used to achieve toxicity were used to induce verapamil toxicity. 3,5 At the end of the verapamil toxicity phase, defined as time zero, the animals received a dose of digoxin, and the verapamil infusion was changed to 4 mg/kg/ hr and continued for five hours to simulate continuous gastrointestinal absorption from a large oral ingestion. Each dog received one dose of digoxin equivalent to 1, 1.5, 2, 3, 4, 6, or 8 times the loading dose of digoxin (0.009 mg/kg).…”

“…We performed a controlled, unblinded laboratory investigation using eight adult male mongrel dogs (19.4-25.3 kg). The dog model was chosen because it previously was used to study verapamil and digoxin [3][4][5] toxicity. The animal care and use committee of the institution approved this protocol, and the care and handling of the animals were in accordance with National Institutes of Health guidelines.…”

“…3,4 In these two previous animal models of verapamil toxicity, digoxin improved hemodynamic parameters compared with calcium alone. These studies used only a single dose of digoxin.…”