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.

A relatively new and novel antidote is increasingly being used to treat highly lipophilic toxicants, such as verapamil. Intralipid 20% was initially used for local anesthetic toxicity. In patients and animal models, dysrhythmias, hypotension, and even cardiac arrest from bupivacaine toxicity were reversed rapidly with intralipid bolus. Three theories on how this works have been proposed. One theory is the lipid forms a “sink” in the vascular compartment that pulls the toxicant from the tissues, where toxicity is occurring, and it becomes trapped and eliminated. The second is that bupivacaine inhibits transport of fatty acids into mitochondria required for energy production, and the exogenous lipids overcome this inhibition. The third is that fatty acids increase calcium in cardiac myocytes and therefore increase inotropy. Generally, boluses are used, but an infusion is sometimes necessary. Unfortunately, the safety of the boluses is unknown, but the complications of intralipid use are generally from prolonged total parenteral infusions.²⁸

Young et al.²⁹ reported a case of a 32-year-old man who ingested 13.44 g of verapamil and bupropion, zolpidem, quetiapine, clonazepam, and benazepril. This patient had refractory hypotension after treatment with intravenous fluids, glucagon, calcium, and norepinephrine. He was then administered 100 mL of 20% intralipid over 20 minutes and then 0.5 mL/kg/hour for almost 24 hours. His blood pressure improved enough in 1 hour to begin weaning the norepinephrine, and the glucagon infusion was discontinued 2 hours after intralipid administration.²⁹ Consultation with a medical toxicologist can be very helpful when considering HIE or intralipid therapy.

Mechanical devices can also serve as adjunctive therapy in calcium channel antagonist poisoning. Transcutaneous or transvenous pacing is indicated when conduction is impaired beyond pharmacologic reversal. More invasive mechanical measures to support the cardiovascular system are an intraaortic balloon pump, extracorporeal membrane oxygenation, and cardiopulmonary bypass.

Often, the lack of mental status impairment coinciding with hypotension can beguile the physician into believing that the patient is not suffering severe clinical effects of a calcium channel antagonist overdose. At this point, elective intubation should be considered, before emergency intubation has to be performed during cardiopulmonary arrest.

Disposition

Asymptomatic patients who have ingested an immediate-release calcium channel antagonist can be monitored for 6 hours in the emergency department. After ingestion of a sustained-release calcium channel antagonist, the asymptomatic patient should undergo cardiovascular monitoring for 18 to 24 hours.³ All symptomatic patients with cardiovascular instability after cardiovascular drug overdose should be admitted to the intensive care unit for cardiovascular monitoring, diagnostic studies, and treatment until the effects have resolved.

Special Considerations: Pediatric Overdose

The 2009 National Poison Center Database System data noted one pediatric fatality of a suicidal 16-year-old girl, who ingested verapamil and an unknown drug.¹ The clinical consequences of accidental pediatric calcium channel antagonist ingestions depend on the dose.

One must consider that the major flaw of studies attempting to demonstrate a dose response of accidental pediatric drug ingestions is that many of the reports are nonexposures. The caretaker of the child may report the exposure to a poison center if a pill is missing and the child is implicated by his or her presence in the vicinity. If the child did not take the drug, the case may be referred to as having a good outcome, and the “dose” considered safe.³⁰

A guideline for pediatric ingestions of calcium channel antagonists states that immediate referral to a health care center is necessary if the dose exceeded the usual therapeutic dose or was considered equal to or greater than the lowest toxic dose (whichever is lower).³ At these doses, significant bradycardia or hypotension may occur. Accidental single ingestions of calcium channel antagonists in children are considered lethal enough to be fatal.³¹

Realistically, administration of activated charcoal is prudent if the patient has presented within 1 hour of the ingestion. Whole-bowel irrigation may be considered for ingestion of a modified-release product but is technically difficult. If the patient is near adult size, has ingested a potentially life-threatening amount of a calcium channel antagonist, and presents within 1 hour of the ingestion, gastric lavage may be helpful for gastrointestinal decontamination. However, many kits are not available, and the “act” of gastric lavage is labor intensive and does not change clinical outcome.

Cardiovascular monitoring for 6 to 8 hours for immediate-release medications and for at least 24 hours for sustained-release medications should reveal delayed toxicity. All symptomatic children should be admitted for cardiovascular monitoring and treated with standard therapy.³

Tips and Tricks

Calcium Channel Antagonist Toxicity

• The patient who presents with undifferentiated hypotension and bradycardia may paradoxically be relatively alert as a result of calcium channel antagonist toxicity, which may cause cerebrovascular vasodilation that is cerebroprotective.

• Insulin is an ideal inotropic agent because it can increase the contractility of the heart without raising oxygen demand.

• Monitor electrolyte concentrations and excess intravenous fluid closely.

• An echocardiogram, central venous pressure monitor, and pulmonary artery catheter can be helpful for diagnosing and treating the multiple components of the shock that occurs during calcium channel antagonist toxicity.

• Continue to monitor serum glucose concentrations after the insulin infusion is discontinued until consistent euglycemia is achieved.

Priority Actions

Treatment of Calcium Channel Antagonist Toxicity

• Consult with a medical toxicologist.

• Intubate hemodynamically unstable patients electively, before emergency intubation is required because of cardiopulmonary arrest.

• Obtain central venous access for fluid resuscitation and administration of pharmaceutical infusions.

• Gastric decontamination is critical in the patient presenting with hemodynamic stability, but it should not be used if the patient is unstable.

• Use hyperinsulinemia/euglycemia (HIE) therapy early (in conjunction with medical toxicology consultation) after intravenous boluses of normal saline, atropine, calcium, and glucagon have failed.

• Titrate the HIE therapy in the same fashion as other standard inotropic medications to obtain a mean arterial pressure of 65 to 75 mm Hg and sings of improving perfusion. Tight glucose control is not the target of treatment.

• Maintain the insulin infusion and taper and stop vasopressor therapy when the mean arterial pressure has achieved 65 to 75 mm Hg and signs of organ perfusion are present.

• If hypoglycemic episodes occur in the setting of hemodynamic stability, decrease the rate of the insulin infusion. If hemodynamic instability occurs, increase the rate of the dextrose infusion.

β-Receptor Antagonists

Pathophysiology

As their name suggests, β-receptor antagonists antagonize the effects of beta agonists by competing for β-adrenergic receptors. The result within the cell is a decrease in cAMP, which inhibits the phosphorylation cascade, thus leading to decreased intracellular flow of calcium and actin-myosin contraction. The effects are bradycardia in the nodal cells and decreased contractility in the cardiac myocytes. Consequently, the attenuated stroke volume combined with a decreased heart rate elicits a decline in cardiac output and the promotion of cardiogenic shock.

β-Receptor antagonism is not the only pharmacologic mechanism of toxicity seen after β-receptor antagonist overdose. α-Receptor antagonism, sodium or potassium channel antagonism, central nervous system penetration leading to seizures with altered mental status, and sympathomimetic stimulation may also occur (Table 148.3).

Table 148.3 Pharmacology of Selected β-Receptor Antagonists

Most of the actively prescribed β-receptor antagonists are first metabolized by hepatic enzymes and then processed by the kidney. One exception is atenolol, which is exclusively excreted in the urine. Atenolol also has a volume of distribution and protein-binding properties that permit hemodialysis as a method of enhancing elimination. Esmolol has the unique metabolic characteristic of rapid metabolism in the serum by red blood cell esterases.

Presenting Signs and Symptoms

Immediate-release products should cause signs and symptoms within 6 hours. Unfortunately, most β-receptor antagonists are of modified-release formulation. They have some pharmacologic effect during the first 6 hours after ingestion, but the peak serum concentration is delayed, and the pharmacologic effect may last longer than with immediate-release formulations.³²

Cardiovascular signs and symptoms are the predominant clinical manifestations of β-receptor antagonist toxicity. As with the calcium channel antagonists, cardiogenic shock results primarily from a decrease in cardiac output secondary to diminished stroke volume and heart rate. Patients may complain of chest pain, shortness of breath, palpitations, and dizziness in relation to their bradycardia and hypotension. The ECG may demonstrate sinus arrest, sinus bradycardia, junctional bradycardia, and all degrees of AV block.

If the β-receptor antagonist also possesses pharmacologic activity at other receptors, the clinical picture will be complicated. α-Receptor antagonism after ingestion of carvedilol or labetalol may contribute to hypotension by causing peripheral vasodilation. Propranolol can cause sodium channel antagonism (membrane-stabilizing effect). This pharmacologic activity is exhibited clinically as a prolonged QRS complex on the cardiac monitor and hypotension, much as in a tricyclic antidepressant overdose. The cardiac rhythm can potentially degenerate into ventricular tachycardia.

Sotalol is infamous for antagonizing the delayed rectifier potassium channels in the myocardium. The results are a prolonged QT interval and a higher risk of torsades de pointes (polymorphic tachycardia), monomorphic ventricular tachycardia, ventricular fibrillation, and asystole. These clinical effects can also be delayed and prolonged. In one case report, the onset of ventricular dysrhythmias occurred 4 to 9 hours after ingestion and did not normalize until 100 hours from the time of ingestion.³³

Observation of sympathomimetic effects after β-receptor antagonist ingestion is rare because of the uncommon clinical use of β-receptor antagonists with intrinsic sympathomimetic activity, such as acebutolol, oxprenolol, penbutolol, and pindolol. Patients who have ingested these agents may have tachycardia, hypertension, tremor, and, possibly, some antidotal efficacy because some beta-antagonists can antagonize their own toxic effects.

Some of the β-receptor antagonists, such as propranolol, are more lipophilic and can cross the blood-brain barrier. Symptoms of delirium, coma, and seizures have been reported in patients with overdose of highly lipophilic β-receptor antagonists. Other less common clinical effects reported are respiratory depression, bronchospasm, hypoglycemia in children, and hyperkalemia.

Tips and Tricks

β-Receptor Antagonist Toxicity

• Obtain a capillary blood glucose measurement to detect euglycemia or hypoglycemia.

• Identify the unique toxicity of each β-receptor antagonist.

• Do not start infusions of glucagon or calcium until multiple boluses have successfully reversed the toxicity.

• Avoid isoproterenol as an antidotal agent.

• Hyperinsulinemia/euglycemia therapy works to treat hypotension from β-receptor antagonist toxicity.

• Atenolol and sotalol have characteristics that allow the use of hemodialysis to enhance elimination.

• Monitor electrolyte concentrations and excess intravenous fluid closely.

• If the beta-blocker is lipophilic (e.g., propranolol), intralipid therapy may be effective at reversing toxicity.

Differential Diagnosis and Medical Decision Making

The differential diagnosis (see also Fig. 148.1) of beta-blocker toxicity includes the following: congestive heart failure and pulmonary edema, cardiogenic or hemorrhagic shock, epidural hematoma, epidural and subdural infections, meningitis, other causes of electrolyte abnormalities, and overdoses of cardiac glycosides, calcium channel blockers, carbamazepine, carbon monoxide, cocaine, and antidepressants.

Measurements of serum concentrations of β-receptor antagonists are generally unavailable and unhelpful in the emergency department. No laboratory studies correlate beta-blocker concentrations with outcomes. Additional standard laboratory testing as for a general overdose is advisable, with particular focus on hypokalemia and hypoglycemia, along with other electrolytes. Cardiac enzymes should be obtained to evaluate for myocardial infarction. Therapeutic interventions and patient stabilization are the priorities. As resuscitation continues, a 12-lead ECG and cardiac monitoring may demonstrate bradycardia, AV conduction abnormalities, and prolonged QRS and QTc intervals. Monitoring for hypocalcemia, hypokalemia, and hypomagnesemia assists in treatment of coexisting causes of prolonged QTc intervals.

Treatment

In a hemodynamically stable patient who has overdosed on a β-receptor antagonist, aggressive gastric decontamination is warranted. The limits of gastric decontamination use in calcium channel antagonist overdose apply to that in β-receptor antagonist overdose.

The end result of overdose of either β-receptor or calcium channel antagonists is shock, despite their different mechanisms of action. Because these agents have a final common pathway, antidotal therapy is analogous. Treatment follows the same algorithm as shown in Figure 148.2. Atropine can be used initially, followed by intravenous calcium, glucagon, HIE, and catecholamines with chronotropic and inotropic effects for refractory bradycardia and AV block. Unfortunately, severe bradycardia and AV block are often refractory to pharmaceutical efforts, and transcutaneous or transvenous pacing may be required.

Calcium reverses toxicity through circumvention of the β-receptor antagonist by entering open L-type calcium channels and increasing the cytoplasmic concentration of calcium, thus leading to contraction of the myosin-actin apparatus. Fear of hypercalcemia should not prohibit the use of elemental calcium as antidotal treatment of β-receptor antagonist toxicity.

Glucagon increases cardiac contractility by bypassing the antagonized β-receptors through activation of cAMP by agonism at the glucagon receptors. This activation increases contractility by activating the phosphorylation cascade, which leads to contraction of actin and myosin. Glucagon also stimulates release of endogenous insulin, a beneficial side effect. Unfortunately, glucagon is often ineffective at reversing β-receptor antagonist toxicity.³⁴

Vasopressin was used in an experimental animal model poisoned by propranolol.³⁵ The investigators discovered equally dismal survival rates for treatment with glucagon and vasopressin.

HIE therapy is a therapeutic approach for β-receptor antagonist toxicity. Animal models demonstrated the superiority of HIE therapy over glucagon, epinephrine, and saline solution for the reversal of the toxic effects of propranolol.³⁶ Yuan et al.¹³ reported effective reversal of the toxic effects of a β-receptor and calcium channel antagonist coingestion with this treatment. Despite the absence of the diabetic ketoacidosis metabolic state produced by calcium channel antagonist, HIE therapy is believed to be just as effective in β-receptor antagonist intoxication. Mechanistically, this antidote improves inotropy by promoting aerobic utilization of glucose by the myocardial myocytes, inhibition of fatty acid metabolism, decreased lactate production, and improvement of myocardial oxygen utilization without increasing oxygen demand. The mild hypokalemia that occurs also may beneficial.¹⁷

The evidence is convincing that HIE therapy is a remedy for a depressed inotropic state, but its reversal of the myriad other toxicologic effects mediated by β-receptor antagonists, such as bradycardia and conduction abnormalities, is unsubstantiated. The clinician must be aware of the limitations of HIE treatment and must treat other toxic effects appropriately. Vigilance in monitoring for the potential adverse effects of HIE therapy in this setting must be greater than for other uses of HIE therapy because of the lack of insulin resistance seen in most β-receptor antagonist intoxications.

A case of cardiac arrest induced by nebivolol, diazepam, and baclofen was reversed with a bolus of intralipid 20% and HIE therapy.³⁷ Intralipid therapy should be considered in lipophilic β-receptor antagonist overdose.

Disposition

The asymptomatic patient who has no cardiovascular effects of overdose with an immediate-release or sustained-release β-receptor antagonist or sotalol can be discharged after 6, 8, or 12 hours of observation, respectively. All symptomatic patients should be admitted for intensive care monitoring of the hemodynamic effects.

Priority Actions

Treatment of β-Receptor Antagonist Toxicity

• Supportive care of airway, breathing, and circulation is the first critical step.

• Gastric decontamination is critical in the patient presenting with hemodynamic stability.

• Administer doses of calcium and glucagon adequate to elicit a clinical response.

• Consider HIE therapy for cardiogenic shock.

• Consider norepinephrine as the first choice for vasopressor therapy.

• Electrical pacing is an option for symptomatic β-receptor antagonist bradycardia.

Digoxin

Pathophysiology

Digoxin is a cardiac glycoside that was historically used for the treatment of congestive heart failure and for rate control in atrial fibrillation. Despite a reduction in popularity, digoxin is still clinically effective for many patients. Natural cardiac glycosides provide another possible exposure source (Box 148.1).

Box 148.1 Natural Cardiac Glycosides

Oleander (Nerium oleander), yellow oleander (Thevetia peruviana)

Lily of the valley (Convallaria majalis)

Foxglove (Digitalis spp.)

Red squill (Urginea maritima)

Dogbane (Apocynum cannabinum)

Skin secretions of Bufo marinus toad

Digoxin pharmacologically alters inotropy and conduction. This agent has the additive effect of increasing automaticity. The results of digoxin therapy are an increase in the intracellular concentration of calcium and higher efficiency of its use by the contractile apparatus. These effects are achieved largely by inhibition of the sodium, potassium adenosine triphosphatase (Na⁺,K⁺ ATP-ase) pump. This pump regulates the intracellular and extracellular concentrations of sodium and potassium by increasing the intracellular potassium concentration and decreasing the intracellular sodium concentration. Digoxin inhibits this function, with resulting serum hyperkalemia and increased intracellular sodium. This effect secondarily impairs the sodium, calcium (Na⁺,Ca⁺⁺) exchange pump, which exchanges extracellular sodium for intracellular calcium. The consequence of this sequence of events is an elevated intracellular calcium concentration, which leads to a dysfunction of intracellular calcium homeostasis and a tetany-like state of the cardiac myocyte. Without myocardial relaxation, an increase in left end-diastolic pressure proceeds to decreased filling and decreased cardiac output, culminating in cardiac failure.

Several clinically important points must be remembered about the pharmacology of digoxin (Table 148.4). The drug is well absorbed, and the onset of action occurs within minutes to hours of administration. The serum digoxin concentration initially is supratherapeutic, until equilibrium between the serum and tissues has occurred. The optimum time for measurement of the serum digoxin concentration is at least 6 hours after ingestion. The volume of distribution is large and the enterohepatic circulation is small, thus rendering methods for enhancing elimination clinically ineffective. These properties effectively make the elimination half-life approximately 36 to 48 hours.^38,³⁹ Most digoxin is eliminated as the parent compound in the urine. Consequently, a decrease in renal function often leads to acute-on-chronic digoxin toxicity in the geriatric patient. The clinician must keep in mind that these pharmacokinetic data are from controlled clinical situations. True toxicokinetic data are difficult to forecast in the patient with digoxin overdose because of inaccuracies about the timing and amount of the dose, comorbidities, drug interactions, and unpredictable variables in the human metabolism of digoxin.

Table 148.4 Pharmacokinetics of Digoxin

Onset of action

Oral: 1.5-6 hr

Intravenous: 5-30 min

Maximal effect

Oral: 4-6 hr

Intravenous: 1.5-3 hr

Intestinal absorption (%)

40-90

Mean: 75

Metabolism Small amount by bacteria in liver and gut Plasma protein binding 25% Volume of distribution (L/kg)

Neonates: 10

Infants: 16

Adults: 6-7

Adults with renal failure: 4-5

Routes of elimination

Renal: 50%-80% unchanged

Hepatic: limited metabolism

Enterohepatic circulation: 7%

Elimination half-life

Anephric patients: >4.5 days

Data from Cave G, Harvey M. Intravenous lipid emulsion as antidote beyond local anesthetic toxicity: a systematic review. Acad Emerg Med 2009;16:815-24; And Wax PM, Erdman AR, Chyka PA, et al. Beta-blocker ingestion: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2005;43:131-46.

Presenting Signs and Symptoms

Patients may be asymptomatic from minutes to hours after ingestion of digoxin. Gastrointestinal symptoms are common, and patients have nausea and vomiting. Patients may complain of changes in vision, especially chromatopsia and xanthopsia. Some mild confusion, weakness, and dizziness also can occur from the direct effect of the digoxin. The cardiac effects are usually represented by symptoms such as palpitations, chest pain, dizziness, and dyspnea. The cardiac signs in acute toxicity are a mixture of bradydysrhythmias, tachydysrhythmias with conductive blockade, and hypotension. Cardiac conduction can be impaired anywhere along the pathway from the sinus node to the AV node and the His-Purkinje fibers. Commonly reported dysrhythmias are listed in Box 148.2. Bidirectional ventricular tachycardia is considered pathognomonic for digoxin toxicity.

The patient with chronic digoxin toxicity is generally older and presents with nonspecific complaints that make diagnosis a challenge. Manifestations can be similar to those of patients with acute digoxin toxicity, but they differ in patients with more neuropsychiatric complaints, such as delirium, confusion, drowsiness, and hallucinations, and visual complaints. Ventricular tachydysrhythmias are more common in patients with chronic toxicity.

The patient with acute-on-chronic toxicity may have clinical manifestations of both the other types of toxicity. In general, acute-on-chronic toxicity is clinically more like acute digoxin toxicity.

Tips and Tricks

Digoxin Toxicity

• If the patient has life-threatening digoxin toxicity, treatment with the digoxin-specific Fab fragments is the first priority.

• Acute-on-chronic and acute digoxin toxicities have the same manifestations, but acute and chronic digoxin toxicities have distinct symptoms, dysrhythmias, and laboratory findings.

• The digoxin serum concentration may be only slightly elevated or normal in chronic digoxin toxicity.

• Digoxin toxicity can manifest as almost any dysrhythmia.

• The equilibrium concentration of serum digoxin occurs 6 hours after ingestion, and is inaccurate after administration of digoxin-specific Fab fragments.

• Recurrence of toxicity is typically related to underdosing of digoxin-specific Fab fragments.

• The indications and treatment of digoxin toxicity and concomitant renal impairment are the same.

• No method of enhancing elimination, including hemodialysis, is effective.

Differential Diagnosis and Medical Decision Making

Before considering digoxin toxicity, one must first define the different types of digoxin toxicity. They are as follows:

Acute digoxin toxicity: A patient who is naive to the medication is exposed to a single acute ingestion.

Acute-on-chronic digoxin toxicity: The serum digoxin concentration increases because of renal failure or an inadvertent or intentional increase in dose. The clinical presentations for this and acute toxicity are similar, so management is similar.

Chronic digoxin toxicity: A patient has clinical signs of digoxin toxicity with a mildly elevated or therapeutic serum digoxin concentration.

The differential diagnosis includes other cardiovascular drugs (see Fig. 148.1), acute renal failure, hypercalcemia, hyperkalemia and hypokalemia, hypernatremia and hyponatremia, and hypomagnesemia.

An ECG and continuous cardiac monitoring are crucial initial steps in determining cardiovascular instability in a patient with digoxin toxicity. These tests alert the clinician to dysrhythmias that require treatment with digoxin-specific Fab fragments and supportive care. A chest radiograph demonstrates any evidence of cardiac failure related to the digoxin overdose.

Laboratory testing should be performed expeditiously in any digoxin overdose, with the focus on serum potassium, magnesium, and digoxin concentrations. Rapid assessment of serum potassium concentration helps determine the severity of the toxicity. In acute digoxin poisoning, the serum potassium value is elevated. If this value is 5 mEq/L or greater, digoxin-specific Fab fragment therapy should be considered.⁴⁰ In chronic digoxin toxicity, the serum potassium concentration is often low, usually because of concomitant ingestion of a diuretic. The hypokalemia, in effect, worsens the inhibition of the Na⁺,K⁺ ATP-ase pump.

Obviously, assessment of the serum digoxin concentration is essential. The therapeutic range is 0.5 to 2.0 ng/mL. The steady-state serum concentration is most accurate 6 hours after ingestion. A serum digoxin concentration of 10 ng/mL at steady state or 15 ng/mL at any time is generally accepted as an indication for digoxin-specific Fab fragment therapy.

A serum digoxin concentration measured in blood collected after administration of digoxin-specific Fab fragments is clinically not useful and is uninterpretable. The assay often measures the antidote, the drug, and the combination of the two, and it interprets one or all of them as the serum digoxin concentration; the result may be higher than, lower than, or within the therapeutic range for serum digoxin.^41,⁴²

Screening for accompanying hypomagnesemia is important because this condition may lead to refractory hypokalemia, blockade of inward calcium channels and intracellular binding sites, blockade of extracellular movement of potassium, decrease in myocardial irritability, and a prolonged QT interval. Hypomagnesemia increases myocardial uptake of digoxin and worsens dysfunction of the Na⁺,K⁺-ATP-ase pump.⁴³

Treatment

A reasonable approach is to consider activated charcoal to minimize intestinal absorption in a person presenting within 1 hour of digoxin overdose. Gastrointestinal decontamination may be limited by emesis induced by the digoxin. Whole-bowel irrigation is also not indicated because of rapid absorption of digoxin and the availability of other, more practical options.

The successful use of digoxin-specific Fab fragments to treat digoxin intoxication was first described in 1976.⁴⁴ Since that time, multiple studies have demonstrated its safety and efficacy.^45,⁴⁶ The best antidote to administer for digoxin toxicity is digoxin-specific Fab fragments, whether for hypotension, dysrhythmias, serum digoxin concentration, or hyperkalemia.

Two commercial formulations of digoxin-specific Fab fragments are available, Digibind and DigiFab. Literature for both products warns against anaphylaxis and administration of the agents to people with papain, chymopapain, or papaya allergies. Other adverse events associated with administration of digoxin-specific Fab fragments occur from removal of the therapeutic benefit of the digoxin—for example, recurrence of congestive heart failure ⁴⁶ or atrial fibrillation with a rapid ventricular response.

After an acute ingestion of digoxin, an empirical bolus of 5 to 10 vials (up to 10 to 20 vials) of digoxin-specific Fab fragments is indicated in the patient with life-threatening toxicity. When the clinical situation allows determination of a serum digoxin concentration, the simple dosing calculation is as follows:

The number obtained is the number of vials needed to treat the patient.

When the amount ingested is known, the digoxin-specific Fab fragment dose can be calculated by knowing that 1 vial will bind 0.5 mg, or multiply the amount ingested by 2 (see Table 148.4 for determining dose). In the noncritical patient, digoxin-specific Fab fragments should be reconstituted with 4 mL of saline, used immediately or within 4 hours if refrigerated, and infused over 30 minutes. Indications for digoxin-specific Fab fragments are listed in Box 148.3. A clinical response should be seen within 60 minutes.⁴⁶

In patients with chronic digoxin toxicity, calculating the dosage of digoxin-specific Fab fragments with the serum digoxin concentration often overshoots the amount needed to reverse toxicity. The concern is precipitating an exacerbation of hypokalemia, congestive heart failure, or rapid atrial fibrillation. A prudent approach is to administer 1 or 2 vials initially. If toxicity has resolved or an adverse effect has occurred, no further vials should be given. If no adverse effect has arisen and toxicity has not resolved, 1 or 2 vials more are indicated.

Many patients presenting with acute-on-chronic digoxin toxicity have renal failure. Digoxin-specific Fab fragments should not be withheld in these patients because of concern about the inability of the kidney to remove the digoxin-Fab complex. This complex cannot be removed by dialysis either. Mild recrudescence of toxicity has been reported when the Fab fragments become unbound and are eliminated faster than digoxin.⁴⁷ However, multiple publications cite inadequate dosing as a much greater risk factor for recrudescence, and the transient rise in serum digoxin concentration has been within the therapeutic range and not clinically significant.^47,⁴⁸ Simply administering another dose of digoxin-specific Fab fragments or giving conscientious supportive care may be the only additional therapy required. These patients typically have transient renal impairment, and once it has resolved, the digoxin, Fab fragments, and Fab-digoxin complex are removed. Finally, the use of digoxin-specific Fab fragments can be cost effective.⁴⁹

Atropine may be effective in treating symptomatic bradycardia early in acute digoxin toxicity because it increases vagal tone. Treatment of bradycardia with atropine later in an acute presentation or in chronic digoxin toxicity is often unsuccessful because the bradycardia is may not be related to vaginal tone but to other toxic effects of the digoxin. The ultimate treatment of symptomatic bradycardia is administration of digoxin-specific Fab fragments.

Transcutaneous pacing and transvenous pacing have been used to treat symptomatic bradycardia, but transvenous pacing must be used with caution. One study reported a higher mortality rate in patients receiving transvenous pacing because of dysrhythmias.⁵⁰ In addition, iatrogenic complications (36%) were seen in patients receiving transvenous pacing.

This danger of transvenous pacing in the setting of digoxin toxicity has come into question, however. A retrospective review of 70 patients was divided into two groups. One group received transvenous pacing, and the other did not. No deaths occurred in the paced group, and 2 patients in the nonpaced group died of ventricular dysrhythmias, but no statistically significant difference was seen. Transvenous pacing was not an independent predictor of prognosis. The investigators reported no complications of venous thromboembolism, cardiac rupture, or infection. The investigators speculated that the previous study had poor outcomes from overdrive transvenous pacing, which can stimulate ventricular dysrhythmias. In their study, the heart rate was limited to 60 beats/minute.⁵¹

Unstable supraventricular or ventricular dysrhythmias can be treated by electrical cardioversion. Because of the hyperexcitability of the digoxin-poisoned myocyte and nodal tissue, however, low current is recommended. The concern is that high voltages may induce refractive lethal ventricular tachycardia.

The use of intravenous calcium in the treatment of hyperkalemia in the digoxin-poisoned patient was considered a contraindication during much of the twentieth century. The concern about calcium administration in digoxin toxicity is an additive toxic effect. During digoxin toxicity, patients already have a dysfunction in intracellular calcium regulation along with an elevated calcium concentration. If more calcium is added to this hypercontractile state, a condition referred to as “stone heart” could be produced. This concern was supported by an early human case series and two animal studies, all published before 1940.⁵²^–⁵⁴

More recently, a case report and animal study found no synergistic effect of calcium and digoxin toxicity resulting dysrhythmia or death during treatment of hyperkalemia.^55,⁵⁶ A retrospective review of 159 patients with digoxin toxicity over 17.5 years compared dysrhythmia in 1 hour from calcium or mortality in the patients treated with calcium versus no calcium. The investigators discovered no dysrhythmias and similar mortality in both groups and increased mortality in patients with higher serum potassium.⁵⁷

An excellent review of the literature on this topic specified that the rate and amount of calcium administered is probably more contributory to dysrhythmias or the stone heart. The reviewers reasonably concluded that if the patient has signs of hyperkalemia toxicity, such as loss of P waves, peaked T waves, or a widened QRS complex, treatment with calcium should be undertaken. If the patient has manifestations of digoxin toxicity such as ectopic beats or ventricular tachycardia, then digoxin-specific Fab fragments should be the first-line treatment.⁵⁸ Ultimately, the anxiety created by calcium combined with digoxin toxicity is probably much greater than the true risk. This risk can be minimized even more by using other methods to decrease the serum potassium. If the patient is hemodynamically stable, administration of digoxin-specific Fab fragments should be the first choice to treat the hyperkalemia and all the other components of digoxin toxicity.

Treatment of hypotension should also include increasing the preload with intravenous fluids and pharmaceutical agents that have inotropic and vasopressor properties, such as norepinephrine. Little is known about the effectiveness of other antidotes, such as glucagon, to treat hypotension or bradycardia. Hypomagnesemia should be treated in standard fashion, with 2 g of intravenous magnesium given over 20 minutes.

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