The 2009 Annual Report of the American Association of Poison Control Centers National Poison Center Database System reported cardiovascular drugs as the second most common cause of fatalities overall (10%), and they were the second fastest in rate of exposure increase.¹ Cardiovascular drugs as a category were ranked as the fifth leading cause of death (44 total deaths: 5 from β-receptor antagonists, 16 from calcium channel antagonists, and 23 from cardiac glycosides). These specific cardiovascular drugs share the clinical effects of hypotension, bradycardia, and conduction disturbances. However, unique differences can help distinguish them in an unknown overdose (Fig. 148.1). Other pharmaceuticals included in the category of cardiovascular agents are angiotensin-converting enzyme inhibitors, antiarrhythmics, clonidine, and other antihypertensives; they are not discussed in this chapter.

Fig. 148.1 Differential diagnosis of cardiovascular drug overdoses.

Calcium Channel Antagonists

Pathophysiology

Calcium channel antagonists block the intracellular flow of calcium ions through L-type voltage-gated calcium channels in myocardial, smooth muscle, and pancreatic beta-islet cells. These mechanisms of action result in cardiovascular toxicity both directly and indirectly. Depending on the selectivity of the calcium channel antagonist, the direct cardiovascular toxicity is a combination of the effects on the cardiac conduction system, myocardial contractility, and vascular smooth muscle vasodilation. The dihydropyridine class (e.g., amlodipine, nifedipine) preferentially acts on the peripheral vasculature, thereby potentially leading to hypotension and reflex tachycardia. Verapamil operates on the sinoatrial and atrioventricular (AV) nodes and on the myocardium. Diltiazem acts to a lesser extent than verapamil on the cardiac tissue and nodes, and it also dilates peripheral vasculature (Table 148.1). The degree of contribution from each mechanism of cardiovascular toxicity can be difficult to predict. Despite the differences in therapeutic mechanisms, the distinctions among families of calcium channel antagonists are often blurred during an overdose, and the patient generally suffers from negative chronotropic, inotropic, and dromotropic effects.²

Table 148.1 Classification of Calcium Channel Antagonists

CLASS	ACTION(S)	EXAMPLE(S)
Phenylalkylamines	Act on sinoatrial and atrioventricular nodes and the myocardium	Verapamil (Calan)
Benzothiazepines	Dilate peripheral vasculature and act to a lesser degree than verapamil on cardiac tissues and nodes	Diltiazem (Cardizem, Tiazac)
Dihydropyridines	Act on peripheral vasculature, leading to hypotension and reflex tachycardia	Nifedipine (Procardia) Isradipine (DynaCirc) Amlodipine (Norvasc) Felodipine (Plendil) Nimodipine (Nimotop) Nisoldipine (Sular) Nicardipine (Vascor)

Calcium channel antagonist overdose also results in indirect toxicity from attenuation of the release of insulin from the pancreatic beta-islet cells. This inhibition leads to hyperglycemia and intracellular catabolism of fatty acids to create energy. The hypoinsulinemia contributes to impairment of cardiac function and shock by preventing the use of glucose as a metabolic substrate. Negative inotropy and diminished peripheral vascular resistance lead to shock and subsequently to metabolic acidosis; the result is a laboratory picture similar to that of diabetic ketoacidosis.

Presenting Signs and Symptoms

Because the calcium channel antagonists were developed to affect the cardiovascular system, the presenting signs and symptoms of overdose with such agents are primarily related to a malfunction of this system. Hypotension is the hallmark of calcium channel antagonist toxicity.

Reflexive tachycardia can occur as a result of peripheral vasodilation after an overdose of a calcium channel antagonist in the dihydropyridine class, but this effect may be transient, and bradycardia usually develops in large overdoses. This tachycardia may prove fortunate in maintaining organ perfusion by sustaining cardiac output when the stroke volume is depleted.

Verapamil and diltiazem overdoses cause bradycardia and numerous conduction abnormalities in and below the AV node. The decreased blood pressure results from vasodilation and decreased cardiac contractility from the negative inotropic and chronotropic effects.²

Patients often complain of chest pain, dyspnea, dizziness, syncope, and palpitations. Other clinical manifestations are confusion, agitation, seizures, pulmonary edema (cardiogenic and noncardiogenic), hyperglycemia, and metabolic acidosis.

Differential Diagnosis and Medical Decision Making

The differential diagnosis (see also Fig. 148.1) for overdose of calcium channel antagonists includes other cardiovascular drugs such as beta-blockers, clonidine, digitalis, and other antidysrhythmics. The emergency physician should also consider myocardial infarction and other causes of cardiogenic shock. The potency of the effect of calcium channel antagonists on the cardiovascular system is astounding. Significant cardiovascular toxicity can occur after supratherapeutic ingestion of calcium channel antagonists. Ingestion of double the therapeutic dose should instigate medical evaluation and treatment. Immediate-release calcium channel antagonists should have some clinical effect within 6 hours. Sustained-release calcium channel antagonists should result in clinical manifestations within 1 to 14 hours.³

Nearly all calcium channel antagonists are manufactured in modified-release formulation. This is convenient therapeutic dosing for the patient, but in overdose, the delayed peak and longer duration of toxicity can have disastrous consequences. The mistakes made by the physician are in finding reassurance in the patient’s normal mental status despite hypotension and in not vigorously monitoring and treating the patient’s hemodynamic condition. If close attention to hypotension is not maintained, the cardiovascular status of the patient will continue to deteriorate until cardiopulmonary arrest becomes imminent. This occurrence has no precise explanation, but investigators have suggested that cerebrovascular vasodilation may be cerebroprotective, acting much like nimodipine does in subarachnoid hemorrhage.

Diagnostic testing is contingent on the necessity of treatment for hemodynamic instability. Once the patient’s airway, breathing, and cardiovascular status have been assessed and stabilized, testing should start with a 12-lead electrocardiogram (ECG) and chest radiography. Rapid determination of hyperglycemia and metabolic acidosis with capillary glucose and arterial blood gas analysis may demonstrate a severe calcium channel antagonist overdose. An elevated serum lactate concentration may be another marker of severe calcium channel antagonist overdose.⁴ Testing for serum concentrations of calcium channel antagonists is not clinically useful or available to guide treatment. Otherwise, standard laboratory testing for a general overdose is a good comprehensive approach.

Treatment

Because significant toxicity can occur after a small overdose of a cardiovascular drug, aggressive gastric decontamination is warranted, with activated charcoal as the primary agent. The general principle is that activated charcoal has the best efficacy if it is initiated within the first hour after ingestion. This is true but often not the circumstance, because most patients present beyond 1 hour from ingestion. If this is the case and the patient is still alert and hemodynamically stable, activated charcoal may prevent absorption, even if more than 1 hour because of sustained- or extended-redease formulation.

Whole-bowel irrigation has been suggested for overdose of calcium channel antagonists because many of these drugs are sustained-release preparations. Whole-bowel irrigation is not indicated for a patient with hemodynamic instability because a significant amount of the drug has already been absorbed,⁵ and, therefore, the opportunity for prevention has passed. In addition, challenging a hypoperfused gastrointestinal system can have disastrous consequences, such as functional and physical obstruction by a calcium channel antagonist bezoar,⁶^–⁹ as well as perforation. Generally speaking, no evidence indicates that any gastric decontamination procedure improves outcome in the patient with an overdose, and the risks must be assessed against the benefits.

Enhanced elimination is the removal of the toxin at a greater rate than inherently done by the body. The modalities are multiple-dose activated charcoal, urinary alkalinization, and some form of hemodialysis. None of these techniques can adequately remove any of the calcium channel blockers or digoxin because of either too great a volume of distribution or protein binding or not enough enterohepatic circulation. Atenolol and sotalol are two β-receptor antagonists with a small volume of distribution and protein binding that could potentially be eliminated by hemodialysis.

The primary focus of treatment is the hypotension. The bradycardia and AV block usually improve as the hypotension improves. Atropine is frequently ineffective because the bradycardia and AV block are not related to increased vagal tone.

An antidotal treatment regimen is provided in Figure 148.2. This regimen emphasizes elemental calcium, either as calcium gluconate (30 mL of a 10% solution, or 3 g of calcium gluconate; 14 mEq elemental calcium) or calcium chloride (10 mL of a 10% solution, or 1 g; 13.5 mEq of elemental calcium). Calcium chloride should be administered through central venous access because it is an acidifying salt, which could cause necrosis of the peripheral vasculature. If the intravenous calcium boluses appear to have improved hemodynamic status, close monitoring for recrudescence of toxicity must be maintained, and further boluses must be given as necessary. An intravenous infusion of calcium is warranted only when it effectively treats the hypotension, and further boluses are required to support the blood pressure (Table 148.2). The serum calcium concentration should be monitored, but antidotal treatment rarely gives rise to clinically significant hypercalcemia.

Fig. 148.2 Treatment of overdose with calcium channel antagonist or β-receptor antagonist.

D₁₀W, 10% dextrose in water; D₅₀W, 50% dextrose in water; IV, intravenous(ly).

Table 148.2 Antidotes, Treatments, Facts, and Formulas for Cardiovascular Drugs

ANTIDOTE OR TREATMENT	DOSING	ADVERSE EFFECTS and signs of improving perfusion
Atropine	Adult: 1 mg IV bolus every 5 min as needed for symptomatic β-receptor antagonist bradycardia (maximum total dose: 0.04 mg/kg or 3 mg) Pediatric: 0.02 mg/kg total dose, minimum of 0.1 mg

Anticholinergic toxicity Glucagon

Adult: 5 mg IV bolus over 2 min (maximum total dose 10 mg)

Adult infusion: 1-5 mg/hr; titrate to MAP of 70 mm Hg

Pediatric: 0.05 mg/kg IV bolus over 2 min (maximum total dose 10 mg)

Pediatric infusion: 0.05 mg/kg/hr to 0.1 mg/kg/hr; titrate to MAP of 70 mm Hg and signs of improving perfusion

Emesis

Hyperglycemia

Calcium chloride (10 mL of 10% solution = 1 g = 13.5 mEq elemental calcium)

Adult: 1-3 g IV (central line) over 10 min as needed for hypotension

Pediatric (27.7 mg/mL of elemental calcium): 5-7 mg/kg of elemental calcium or 0.2-0.25 mL/kg IV (central line) over 10 min as needed for hypotension

Infusion: 20-50 mg/kg/hr

Sclerosis of veins

Hypercalcemia

Calcium gluconate (10 mL of 10% solution = 1 g = 4.65 mEq elemental calcium)

Adult: 3-9 g IV (central line) over 10 min as needed for hypotension

Pediatric: (9 mg/mL of elemental calcium) 5-7 mg/kg of elemental calcium or 0.6-0.8 mL/kg

Infusion: 20-50 mg/kg/hr

Hypercalcemia Norepinephrine (α₁ and β₁ agonist) Start at 0.1 mcg/kg/min; titrate to MAP of 70 mm hg and improvement in perfusion

Dopamine

For vasodilation of renal and splanchnic vasculature: 1-5 mcg/kg/min

For β₁ agonist: 5-10 mcg/kg/min

For α₁ agonist 10-20 mcg/kg/min

Same as for norepinephrine Epinephrine (α₁, β₁, and β₂ agonist) Start at 1 mcg/min; titrate to effect Same as for norepinephrine Dobutamine (β₁ agonist) 2.5 mcg/kg/min to 15 mcg/kg/min Same as for norepinephrine Isoproterenol (β₁, β₂ agonist)

Start at 0.02 mcg/kg/min; titrate to effect

— Insulin (regular)

Consultation with a clinical toxicologist is recommended

Give a bolus of 1.0 units/kg IV with 1 ampule of D₅₀W

Immediately start an infusion of 1.0 units/kg/hr with a glucose infusion of D₁₀W at 100 mL/hr

Titrate 0.5 units/kg every 30 min until desired effect; 1 ampule of D₅₀W can be given during every increase in infusion; titrate to desired effect when blood pressure has reached desired value and signs of improving perfusion

When the blood pressure has reached the desired value with the insulin infusion, taper and wean pressor agent therapy

Monitor serum glucose concentration every 15 min for the first 60 min; when stable, monitor every 60 min thereafter

Monitor serum potassium and other electrolyte concentrations every 60 min

Hypoglycemia

Hypokalemia

Volume overload

Intralipid 20%

Bolus: 1.5 mL/kg repeated as needed for cardiovascular instability

Infusion: 0.25 mL/kg/min as needed for cardiovascular instability

Antineutrophil activity

Pancreatitis

Elevated liver enzymes

Acute lung injury

Intravenous crystalloid 20 mL/kg IV; repeat again if blood pressure has not improved Pulmonary edema with severe cardiogenic shock Vasopressin (V₁, V₂ receptor agonist) 0.01-0.04 units/min; titrate to effect along with administration of 1-2 catecholamine vasopressors

Ischemia

Water intoxication

Phosphodiesterase inhibitor (Milrinone) Give 50 mcg/kg IV bolus over 2 min; then 1.0 mcg/kg/min — Digoxin-specific Fab fragments

For acute overdose (unknown amount in adult or child): 5-10 vials IV as a bolus; repeat as needed every 30 min

For chronic overdose in adult or child: 1-2 vials IV as a bolus; repeat as needed every 30 min

If amount ingested is known: 1 vial binds 0.5 mg of digoxin

Dosage calculated from serum digoxin concentration:

Anaphylaxis

Removal of therapeatic effect of digoxin on cardiovascular disease

Mechanical devices

Intraaortic balloon pump

Cutaneous or transvenous pacing

Extracorporeal membrane oxygenation

Cardiopulmonary bypass

—

D₁₀W, 10% dextrose in water; D₅₀W, 50% dextrose in water; IV, intravenous(ly); MAP, mean arterial pressure.

Next, glucagon, in 5-mg intravenous boluses for two doses, may theoretically increase cardiac contractility by bypassing the antagonized calcium channels. When glucagon binds to its receptor, it activates cyclic adenosine monophosphate (cAMP). This may increase contractility by activating the phosphorylation cascade, which results in contraction of actin and myosin. Glucagon also stimulates release of endogenous insulin, a fortunate side effect explained later. Like a calcium infusion, a glucagon infusion is warranted only if a beneficial effect is seen after several boluses have been given. Glucagon can cause emesis because of relaxation of the lower esophageal sphincter.

Hyperinsulinemia euglycemia (HIE) therapy and catecholamines with inotropic and vasopressor activity are the next line of treatment for refractory hypotension in calcium channel antagonist overdose, but inotropics and vasopressors will be discussed first. A multicenter study compared dopamine and norepinephrine agents in all patients categorized as being in shock, regardless of cause. No difference was seen in the outcome (death at 28 days) for all patients in the study, but a predetermined subgroup analysis found greater mortality in patients with cardiogenic shock who were treated with dopamine.¹⁰ Because calcium channel antagonists can cause cardiogenic shock, norepinephrine is probably a good first choice. If clinically significant hypotension persists, adding more agents may be necessary. Cardiovascular data from diagnostic modalities such as transthoracic echocardiogram, pulmonary artery catheter, arterial catheter, and central venous catheter should dictate which cardiovascular agent is the most appropriate choice. Vasopressin has been used in human cases when peripheral vasoconstriction is indicated.¹¹ Worsening of the cardiac index was demonstrated when vasopressin was used in an animal model to treat hypotension induced by calcium channel antagonist.¹²

In 1999, Yuan et al.¹³ described the first published use of high-dose insulin-euglycemia (HIE) therapy, in four patients with verapamil overdose and in one patient with amlodipine and atenolol overdose. HIE promotes inotropy by improving myocardial energy production. In addition, insulin has antiinflammatory attributes that protect against apoptosis and ischemic reperfusion injury.²

Subsequently, numerous case reports, reviews, and HIE regimens were published.^2,¹⁴^–¹⁹ HIE therapy has successfully reversed cardiogenic shock from a polydrug overdose,²⁰ and historically it was used in multiple nontoxicologic conditions, such as acute myocardial infarction, post–cardiac surgery status, and septic shock.²¹ The superiority of HIE therapy for cardiogenic shock resulting from calcium channel antagonist toxicity was also demonstrated dramatically in animal models.²²^–²⁵

Failure of HIE therapy often occurs when it is started as rescue therapy and when the dose is inadequate.²⁶ A small prospective observational study of patients treated with HIE therapy supports it safety.²⁷ HIE therapy should be started when boluses of calcium, glucagon, atropine, and intravenous fluids have failed and the physician is considering a pressor agent to improve refractory hypotension. The call to the pharmacist to obtain the HIE infusion should be made when the norepinephrine infusion is begun.

HIE therapy should start with a 1.0 unit/kg bolus of regular insulin followed by an intravenous injection of 1 ampule of 50% dextrose in water (D₅₀W). Immediately thereafter, an infusion of 1.0 unit/kg/hour of regular insulin should begin, along with an infusion of D₁₀W at 100 mL/hour. Serum glucose levels should be monitored every 15 minutes during the first hour and then, if stable, every hour. A serum electrolyte analysis must be performed every hour to monitor serum potassium, glucose, and other electrolyte values. Clinically significant hypoglycemia has not been described with HIE therapy. The amount of intravenous fluid administered must be taken into consideration and the patient closely monitored for signs and symptoms of pulmonary edema because the calcium channel antagonist overdose can result in cardiogenic or noncardiogenic pulmonary edema. The clinician must also be cognizant of the limitations of HIE therapy in patients with bradycardia, conduction abnormalities, and hypotension secondary to vasodilation.

When hemodynamic stability has been achieved, the vasopressor therapy should be tapered and stopped because of the potential detrimental effect on the myocardium from increased oxygen demand and metabolic acidosis. Consequently, HIE therapy can be gradually reduced when the patient becomes hemodynamically stable. After the insulin has been discontinued, the serum glucose concentration must be monitored continually for 4 to 6 hours after discontinuation of insulin.

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