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Calcium Channel Blocker Toxicity

By Nancy G. Murphy, MD

Introduction

Calcium channel blockers (CCB) are used extensively for treatment of hypertension, angina pectoris, tachyarrhythmias and migraine prophylaxis. Reports of serious CCB toxicity have increased due to the widespread use of this class of medication. In addition, ingestion of sustained release preparations can result in delayed and prolonged toxicity.

Case presentation

A 42 year old man presented four hours after a suicidal ingestion of verapamil. En route to the hospital, the patient had normal vital signs and was awake and alert. Upon arrival to the emergency department, a single dose of activated charcoal (60 gm) was administered orally and the patient was placed on a cardiac monitor. His heart rate was 80 beats per minute and the blood pressure was 120/80 mm Hg. Within an hour, the patient became lethargic and both pulse rate and blood pressure began to decline rapidly. The rhythm strip showed a slow junctional rhythm with occasional sinus beats:

rhythm strip

Atropine had no effect on his heart rate of 40 bpm and intravenous fluids did not improve his blood pressure of 70/40 mmHg. Glucagon, 5 mg IV, and calcium chloride (total of 5 ampules of 10% solution) had no effect on his hemodynamics, nor did transcutaneous pacing. A bolus of insulin and dextrose were also administered with minimal effect as dopamine and norepinephrine were started. Finally, a transvenous pacemaker was inserted, with subsequent normalization of his heart rate and blood pressure. Intravenous drugs were eventually weaned and the patient recovered with no further events. He was transferred to psychiatry on hospital day # 4.

Questions

  1. What is the pathophysiology of CCB poisoning and what are the typical presenting symptoms and signs?
  2. What decontamination procedures should be performed for acute CCB overdose?
  3. When can a patient be safely medically cleared?
  4. What are the treatment options for CCB toxicity?

Pathophysiology

CCBs block intracellular entry of calcium by binding L-type calcium channels located primarily in cardiac and vascular smooth muscle. The results include decreased rate of firing of the sinus node pacemaker, decreased rate of conduction through the AV node, decreased cardiac contractility, and decreased vascular tone. Different CCBs have varying degrees of effect on these physiologic functions: verapamil has depressive effects predominantly on SA/AV nodal conduction and myocardial contractility. Diltiazem is similar in action to verapamil but produces less cardiac depression at therapeutic doses. Nifedipine and other dihydropyridines act preferentially on vascular smooth muscle, resulting in vasodilation; their effect on cardiac conduction is insignificant in therapeutic doses. However, in overdose, the selectivity of specific agents may be lost. Extracardiac effects of CCB’s include lethargy, confusion, seizures (rare), hyperglycemia and lactic acidosis from hypoperfusion.

Clinical presentation

The cardiac manifestations of CCB toxicity are essentially an extension of their therapeutic effects. Serious toxicity can occur even with therapeutic doses of CCB’s in persons with underlying cardiac disease, and similar effects are observed in healthy people after overdose. Hypotension is a common feature of CCB overdose and results from different mechanisms. Vasodilation can result in hypotension due to decreased systemic vascular resistance; this is an effect of all CCB’s. Other mechanisms of hypotension are severe bradycardia and depressed contractility that lead to decreased cardiac output and shock. Inhibition of calcium entry into the myocardial cell, which is necessary for muscle contraction, results in depressed myocardial contractility. Verapamil- and diltiazem-induced depression of slow-response cardiac cells can also result in sinus bradycardia or arrest and AV block, particularly in the setting of preexisting cardiac conduction disease.

Diagnosis

Hypotension and bradycardia, especially in the presence of sinus arrest or AV block and in the absence of QRS prolongation, should raise suspicion regarding CCB toxicity. The differential diagnosis should include beta-receptor blocking agents and other sympatholytic drugs, as well as digoxin (which can cause bradyarrhythmias). Laboratory studies should include electrolytes, glucose, BUN, creatinine, digoxin level (if applicable) and lactate level if acidosis is present. ECG and pulse oximetry monitoring are crucial.

Treatment

Initial treatment measures for CCB toxicity include appropriate airway management, assessment of vital signs, and continuous cardiac monitoring. Activated charcoal should be administered as soon as possible, and some sources have advocated repeat doses for sustained-release products, although the efficacy of multidose charcoal is unproven. Gastric lavage may be useful if the ingestion occurred within one hour prior to treatment and the product is not an immediate-release preparation. Whole bowel irrigation is the preferred gastrointestinal decontamination procedure following ingestions of sustained-release medications, unless the patient is hemodynamically unstable or has an ileus.

Pharmacological management of CCB toxicity may include use of atropine, calcium, glucagon, dopamine, epinephrine, norepinephrine, inamrinone (or other phosphodiesterase inhibitor), and combined high-dose insulin-glucose therapy. Recommendations for treatment are based on relatively few animal studies, case reports and case series, and empiric or clinical experience. It should be emphasized that there is no single, predictable “antidote” for CCB poisoning. Generally, therapy should be directed at the likely mechanism of toxicity.

Bradycardia

For bradycardia refractory to atropine, glucagon 5-10 mg IV bolus can be administered, followed by an infusion of 5-10 mg/hour. There are case reports and some anecdotal experience with glucagon improving conduction in these cases, but clinical trials supporting its use are lacking. Cardiac pacing can also be effective, but may not result in “capture” or electrical signal conduction may be impaired, and there is no guarantee that capture will improve contractility and blood pressure.

Hypotension

Hypotension can be due to vasodilation or negative inotropy or both. It may be difficult to determine which mechanism is involved in a given patient without placing a Swan-Ganz line and measuring cardiac output and calculating peripheral vascular resistance. However, an empiric trial-and-error approach is often taken. Vasodilation is treated with IV fluids and direct vasoconstrictors such as norepinephrine or phenylephrine.

Negative inotropic effects may be reversed by a number of treatments.

  1. Calcium can reverse the negative inotropic effects of CCB’s, and may partially reverse the electrophysiologic toxicity but appears to have no effect in reversing vasodilation. The effective dose of calcium has been debated. In general, initial IV boluses of calcium (one gram of either calcium gluconate or chloride) followed by continuous infusion with monitoring of serum calcium is a reasonable approach, using the hemodynamic profile as a guide for dosing. Aim for a serum calcium of about 13-15 mg/dl, at least initially. High-dose calcium administration has been described in CCB overdose resulting in transient serum calcium levels as high as 23.8 mg/dl with no apparent adverse effect. Calcium chloride provides more available calcium per gram than calcium gluconate. Care should be taken to prevent extravasation of calcium chloride into the tissues as skin necrosis may occur. As a result, central lines may be the preferred route for calcium chloride infusions. Calcium gluconate does not carry the same risk of skin injury if extravasation occurs. (Note: it may be dangerous to administer calcium to a patient with digoxin toxicity; older literature suggests that arrhythmias may occur. More recent studies have provided conflicting results.)
  2. In patients not immediately responding to calcium, an infusion of dopamine (5-20 mcg/kg/min) or epinephrine (1 mcg/min titrated upwards as needed) may provide beta-1-mediated inotropic support. Inamrinone (0.75 mg/kg followed by infusion at 5-10 mcg/kg/min) has also been administered with some success.
  3. High dose insulin (with co-administration of glucose to maintain euglycemia) can significantly improve myocardial contractility when standard therapies have failed. Insulin has inotropic activity and allows the myocardium to utilize energy, in the form of carbohydrates, more efficiently. The result is increased myocardial contractility and improvement of hypotension. The suggested dose of insulin is 0.5-1.0 units/kg/hr, which is much higher than the doses used to treat diabetic ketoacidosis. Concomitant administration of dextrose is required: for the first hour, a reasonable dose estimate is 25 g IV, titrated according to blood glucose measurements. Average requirements range between 20-30 g/hour.
  4. Glucagon can have positive inotropic effects in patients with beta-receptor blocker poisoning, and it is possible that some hypotensive CCB-poisoned patients may respond with elevations in blood pressure, although there are no clinical trials to support this. Glucagon should be administered at doses of 5-10 mg as a bolus, followed by an infusion of 5-10 mg/hour if bolus dosing is effective.
  5. Pacing, intra-aortic balloon pumps and extracorporeal bypass have been used for refractory shock in this setting.

Discussion of case questions and key points

  1. CCB’s block entry of calcium into cells, resulting in peripheral and coronary vasodilation, reduced cardiac contractility, slowed AV conduction and sinus node depression. Clinically, this commonly results in bradycardia and hypotension.
  2. Aggressive gut decontamination may be lifesaving if initiated soon after overdose. Activated charcoal is effective in binding CCB’s. Whole Bowel Irrigation (at a rate of 2 L/hour) should be used in patients with overdoses of sustained-release products, as long as the patient is hemodynamically stable and has no ileus.
  3. An asymptomatic patient with an ingestion of an immediate release CCB should be observed on a cardiac monitor for at least 6-8 hours. The observation period should be extended to 12-24 hours if the patient ingested a sustained-release CCB. The longer duration (24 hours) is recommended if the ingestion was sustained-release verapamil.
  4. There is no “magic bullet” antidote for CCB poisoning. Treatment options for CCB-induced bradycardia include atropine, cardiac pacing, and possibly calcium and glucagon. Hypotension should first be treated with intravenous fluids, then calcium, insulin/dextrose and vasopressors. Refractory cases may benefit from pacing, intra-aortic balloon pump, or extracorporeal bypass.