Cardiovascular Drugs

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Chapter 152

Cardiovascular Drugs

Jon B. Cole and David J. Roberts

Cardiovascular drugs are a common cause of poisoning in the United States; in 2010, 97,336 exposures to cardiovascular drugs were reported to U.S. Poison Control Centers.¹ Cardiovascular drugs are the second most common cause, accounting for more than 10%, of all poisoning deaths in the United States. Of the scores of cardiovascular drugs, three classes—cardioactive steroids (primarily digoxin), beta-adrenergic blockers, and calcium channel blockers—account for the majority of fatalities.

Cardioactive Steroids (Digoxin)

Perspective

Digoxin is derived from the Balkan foxglove plant, Digitalis lanata (Fig. 152-1), and the trade name for digoxin (Lanoxin) is derived from the Latin name of this plant.² Digitoxin, which is no longer in clinical use, comes from Digitalis purpurea.² Although William Withering was the first to describe the medicinal use of the foxglove plant,³ the ancient Egyptians reference medicinal use of foxglove. Despite centuries of experience with digitalis, chronic and acute poisonings still occur. Controversy about the therapeutic benefit of cardioactive steroids is not new. Benjamin Rush wrote in 1797, “I suspect the cases in which [digitalis preparations] were useful to have been either so few or doubtful and that the cases they had done harm were so much more numerous and unequivocal as justly to banish them from the Materia Medica.”⁴ Medication errors and toxic effects account for the most common causes (44%) of preventable iatrogenic cardiac arrests.

Figure 152-1 The Balkan foxglove plant, from which digoxin is derived.

Principles of Disease

Pathophysiology

Digoxin is used therapeutically (1) to increase the force of myocardial contraction to increase cardiac output in patients with heart failure and (2) to decrease atrioventricular (AV) conduction to slow the ventricular rate in atrial fibrillation. The basis for its first effect is inhibition of membrane sodium-potassium–adenosine triphosphatase (Na⁺,K⁺-ATPase), which increases intracellular sodium and extracellular potassium concentrations. This increase in intracellular sodium concentration results in dysfunction of the sodium-calcium ion exchanger, which normally extrudes intracellular calcium after systole. This subsequent increase in intracellular calcium concentration results in a larger amount of calcium pumped into the sarcoplasmic reticulum, so that on calcium-induced calcium release during subsequent action potentials, a larger amount of calcium is released into the cell, causing a more powerful contraction and thus increased cardiac output. Any molecule with this effect is classified as a cardioactive steroid. Cardiac glycosides (such as digoxin) are merely cardioactive steroids with additional sugar moieties attached to their steroid nucleus. At therapeutic doses, the effects of digoxin on serum electrolyte levels are minimal. With toxic levels, digoxin paralyzes the Na⁺,K⁺-ATPase pump, potassium cannot be transported into cells, and serum potassium concentration can rise as high as 13.5 mmol/L.⁵

Digoxin exerts direct and indirect effects on sinoatrial (SA) and AV nodal fibers. At therapeutic levels, digoxin indirectly increases vagal activity. At toxic levels, digoxin can directly block the generation of impulses in the SA node, depress conduction through the AV node, and increase the sensitivity of the SA and AV nodes to catecholamines. Catecholamines, whether endogenous or administered to treat bradydysrhythmias or hypotension, probably play an important role in digoxin toxicity. Because bradydysrhythmias and tachydysrhythmias can appear and alternate in the same patient, administration of drugs to treat tachycardias may later contribute to more refractory bradycardias and AV block.

Digoxin also exerts three primary effects on Purkinje fibers: (1) decreased resting potential, resulting in slowed phase 0 depolarization and conduction velocity; (2) decreased action potential duration, which increases sensitivity of muscle fibers to electrical stimuli; and (3) enhanced automaticity resulting from increased rate of phase 4 repolarization and delayed afterdepolarizations. These mechanisms account for an increase in premature ventricular contractions, the most common manifestation of digoxin toxicity. At toxic extremes, these effects result in a dangerous sensitivity to mechanical and electrical stimulation. Interventions with pacemaker wires, catheters, and cardioversion can result in asystole, ventricular tachycardia, and ventricular fibrillation.⁶

Unlike most cardiovascular drugs, digoxin can produce virtually any dysrhythmia or conduction block, and bradycardias are as common as tachycardias (Box 152-1). Unfortunately, none is unique to digoxin, and because they can all occur in the setting of ischemic and other heart disease, digoxin toxicity remains a clinical rather than an electrocardiographic diagnosis.

The volume of distribution (V_d) of digoxin is 5 L/kg for adults but varies from 3.5 L/kg in premature infants to 16.3 L/kg in older infants.⁷ This indicates that only a small fraction of digoxin remains in the intravascular space, and the drug is highly concentrated in cardiac tissue. The myocardial-to-serum ratio at equilibrium ranges from 15 : 1 to 30 : 1. The V_d for digitoxin is only 0.5 L/kg, giving it a different pharmacokinetic profile.

The elimination half-life of digoxin, which is primarily excreted in the urine, is 36 hours, and the half-life of digitoxin, which is metabolized in the liver, is 7 days. Whereas digoxin undergoes only a small enterohepatic circulation, that for digitoxin is large, and multiple-dose activated charcoal treatment has been used for digitoxin.

Protein binding varies from 20 to 30% for digoxin to 95% for digitoxin. The significant protein binding and large volumes of distribution suggest that hemodialysis, hemoperfusion, and exchange transfusion are ineffective. The long half-lives suggest that temporizing measures such as pacemakers, atropine, and antidysrhythmic drugs would cost more time, money, and lives than simply giving Fab fragments initially.

Multiple drugs and disease states can negatively alter absorption, V_d, protein binding, and elimination and render the heart more susceptible to digoxin toxicity. The factors listed in Box 152-2 are especially important risk factors in chronic intoxication.

Clinical Features

The symptoms and signs of chronic digoxin toxicity are nonspecific. The most common symptoms, in more than 80% of cases, are nausea, anorexia, fatigue, and visual disturbance, but a variety of gastrointestinal, neurologic, and ophthalmic disturbances also occur (Box 152-3). Digoxin intoxication should be considered in any patient receiving maintenance therapy who has consistent symptoms, especially with new conduction disturbances or dysrhythmias.

There are significant differences between acute and chronic toxicity (Table 152-1). Chronic poisoning has an insidious onset and is accompanied by a higher mortality rate that is probably due in part to underlying heart disease and chronic accumulation of the toxin. In cases of chronic intoxication, the LL₅₀ (the level with a 50% mortality) is only 6 ng/mL.⁸ The LL₅₀ for acute intoxication is not known, but it is certainly much higher, especially in children. The association of hyperkalemia with acute toxicity is obvious given the mechanism of digoxin; either hypokalemia or hyperkalemia may occur with chronic toxicity.

Table 152-1

Chronic versus Acute Digitalis Intoxication

CHRONIC	ACUTE
Higher mortality (LL₅₀ 6 ng/mL)	Lower mortality
Ventricular dysrhythmias more common	Bradycardia and atrioventricular block more common
Usually elderly patients	Usually younger patients
Often need Fab fragment therapy	Often do well without Fab (Caution: many exceptions)
Underlying heart disease increases morbidity and mortality	Absence of heart disease decreases morbidity and mortality

Diagnostic Strategies

Diagnosis and management rely heavily on serum digoxin levels, but it is the steady state, rather than peak concentration, that correlates with tissue toxicity and is used to calculate antidote dosages. Peak concentrations after an oral dose of digoxin occur in 1.5 to 2 hours, with a range of 0.5 to 6 hours.⁹ Steady-state serum concentrations are not achieved until after distribution, or 6 to 8 hours after a dose or overdose, and may be only one fourth to one fifth of the peak concentration. The ideal serum digoxin concentration for patients with heart failure is considered to be 0.7 to 1.1 ng/mL,¹⁰ although laboratory “normals” are often reported up to 2.0 ng/mL. Serum steady-state digoxin levels of 1.1 to 3.0 ng/mL are equivocal; that is, levels as low as 1.1 ng/mL have been associated with increased mortality,¹¹ and patients with levels up to 3.0 ng/mL can be asymptomatic.¹² The incidence of digoxin-incited dysrhythmia reaches 10% at a level of 1.7 ng/mL and rises to 50% at a level of 2.5 ng/mL. Determination of a level too soon after the last maintenance dose falsely suggests toxicity, especially in cases of chronic intoxication, in which significant morbidity and mortality can occur at levels of 2 to 6 ng/mL.¹⁰ After an acute massive overdose in a patient who is rapidly becoming symptomatic, however, it may be impractical to wait 6 to 8 hours for the first reading.¹³ It is unlikely that early levels exceeding 10 to 20 ng/mL will fade to clinical insignificance at 6 to 8 hours after ingestion.

Differential Considerations

No sign or symptom, including dysrhythmia, is unique to digoxin poisoning, so the differential diagnosis is broad. Intrinsic cardiac disease as well as other cardiotoxic drugs should be considered. Central nervous system (CNS) depression or confusion may be due to various depressant drugs and toxins as well as infection, trauma, inflammation, and metabolic derangements. Visual disturbances should be binocular and are often not reported by the patient. Gastrointestinal disturbances are common and nonspecific and may be misdiagnosed as gastritis, enteritis, or colitis.

Management

Fab Fragments (DigiFab)

The treatment of significant digoxin poisoning is the administration of digoxin-specific fragment antigen-binding (Fab) antibodies (DigiFab); all other interventions are considered complementary.

The mortality rate before Fab fragment therapy was 23% despite all of the interventions described.¹⁴ Fab fragment treatment is well established in both chronic and acute poisonings, with a 90% response rate.¹⁵ Nonresponders usually receive too little antibody or receive it too late. Other nonresponders are compromised by underlying heart or multisystem disease.

Digitalis antibodies are derived from sheep, but allergic reactions occur in less than 1% of cases.¹⁵ Reactions have included erythema, urticaria, and facial edema, all of which are responsive to the usual treatment. Other expected reactions when Fab fragments neutralize digitalis include hypokalemia, exacerbation of congestive heart failure, and increase in ventricular rate with atrial fibrillation. Two Fab fragment preparations were previously available; however, Digibind has been discontinued, leaving DigiFab as the only available product in the United States. If vials of Digibind are still available at a given institution, they require a 0.22-µm membrane filter for proper use; such a filter is not required for DigiFab.

Fab fragment treatment is best reserved for cases of serious cardiovascular toxicity rather than for routine or prophylactic administration with higher than expected serum levels. In acute poisoning, antibody treatment should be used for a serum potassium level above 5.0 mEq/L or unstable dysrhythmias, such as symptomatic sinus bradycardia, ventricular dysrhythmias, or second- or third-degree heart block unresponsive to atropine. Although toxicity increases with greater body load, there is no clear correlation with amount ingested, especially in children, and many patients with large ingestions or high serum levels become only mildly symptomatic.⁸ Fab fragment therapy should be used before transvenous pacing, which carries significant risk.

The median time to initial response is 19 minutes after completion of the Fab infusion, but complete resolution of digitalis toxic rhythms may require hours.16,17 Late administration of Fab fragments has resuscitated 54% of patients who have suffered cardiac arrest.¹⁸ This antidote should be considered whenever hemodynamic compromise attends a digitalis toxic dysrhythmia or heart block (Box 152-4).¹⁹

BOX 152-4 Recommendations for Administration of Digitalis Antibody Fragments

Adults

1. Ventricular dysrhythmias more severe than premature ventricular contractions

2. Progressive and hemodynamically significant bradydysrhythmias unresponsive to atropine

3. Serum potassium level above 5.0 mEq/L

4. Rapidly progressive rhythm disturbances or rising serum potassium level

5. Coingestion of cardiotoxic drugs such as beta-blockers, calcium channel blockers, or tricyclic antidepressants

6. Ingestion of plant known to contain cardiac glycosides plus severe dysrhythmias (rare)

7. Acute ingestion of more than 10 mg plus any one of factors 1 through 6 above

8. Steady-state serum digoxin concentration above 6 ng/mL plus any one of factors 1 through 6 above

Children

1. Ingestion of more than 0.1-0.3 mg/kg or steady-state digoxin concentration above 5 ng/mL plus rapidly progressive symptoms or signs of digitalis intoxication or potentially life-threatening dysrhythmias or conduction blocks or serum potassium concentration above 6 mmol/L

2. Coingestion of other cardiotoxic drugs with additive or synergistic toxicity

3. Ingestion of plant known to contain cardiac glycosides plus severe dysrhythmias (rare)

Current formulas for calculation of DigiFab doses are found in the package insert. There are at least three approaches. The first is empirical. A patient has a history of digitalis ingestion, consistent symptoms, and life-threatening dysrhythmias. There is no time to assess serum digoxin levels, and 10 vials should be administered over 30 minutes for the average acute ingestion, 4 to 6 vials for the average chronic ingestion. In cardiac arrest, 20 vials can be administered undiluted by intravenous bolus. The second approach uses a simple calculation when the ingested dose is known with reasonable certainty. One vial of Digibind or DigiFab contains 38 mg or 40 mg, respectively, of Fab fragments, which bind 0.5 mg of digoxin or digitoxin (Box 152-5). A third approach is to base the dosage on the steady-state serum digoxin or digitoxin level after 6 to 8 hours (Boxes 152-6 and 152-7). Because most assays measure both bound and unbound drug, digoxin levels will be elevated for up to 1 week, with values often greater than 100 ng/mL once Fab fragments have been administered. Newer methods can measure free digoxin, but it is more meaningful to follow the patient clinically.

BOX 152-5 Sample Calculation of Digibind or DigiFab Based on Ingested Dose of Digoxin or Digitoxin *

Case: A toxic-appearing 40-year-old woman has ingested fifty 0.25-mg digoxin tablets.

^*Formula from GlaxoSmithKline, 2008.

BOX 152-6 Sample Calculation of Digibind or DigiFab Based on Steady-State Digoxin Concentration *

Case: A toxic-appearing 4-year-old child weighing 20 kg has a digoxin level of 16 ng/mL 8 hours after ingestion of an unknown number of digoxin tablets.

^*Formula from GlaxoSmithKline 2008; assumes V_d = 5 L/kg.

BOX 152-7 Calculation of Digibind or DigiFab Based on Steady-State Digitoxin Concentration *

Case: A toxic-appearing 70-year-old man weighing 80 kg has a digitoxin level of 200 ng/mL (therapeutic = 10 to 35 ng/mL).

^*Formula from GlaxoSmithKline 2008; V_d = 5 L/kg.

Electrolyte Correction

In cases of chronic toxicity, which may be exacerbated by hypokalemia, maintenance of the serum potassium level to at least 3.5 to 4 mEq/L is an important early treatment. Potassium can be administered orally (which is safer) or intravenously (IV) at a rate of less than 40 mEq/hr.

In acute poisoning, serum potassium concentration may begin to rise rapidly within 1 to 2 hours of ingestion. Potassium should be withheld, even if mild hypokalemia is measured initially. The initial serum potassium concentration may in fact be a better predictor of mortality than the initial digoxin concentration. In a study of 91 patients with acute digoxin poisoning, nearly 50% of the patients with serum potassium concentrations between 5.0 and 5.5 mmol/L died. No patients with a potassium level of less than 5.0 mEq/L died, and all 10 patients with serum potassium concentrations exceeding 5.5 mmol/L perished.²⁰ Because of these findings, a serum potassium concentration greater than 5 mmol/L alone warrants treatment with Fab fragments. Even with Fab fragments, severe hyperkalemia should be treated with intravenous administration of glucose, insulin, and sodium bicarbonate as needed.

The decision to administer calcium to patients with hyperkalemia and digoxin poisoning represents a clinical dilemma. Classic teaching is that in the setting of the increased intracellular calcium concentration from digoxin poisoning, administration of exogenous calcium will result in “stone heart” from excessive intracellular calcium.²¹ This concept has been in the literature since 1927,²² based on animal studies.²³ Documented cases of cardiac arrest after calcium administration are exceedingly rare in the literature, and the temporal relationship is dubious.²⁴ More recent data indicate that the intravenous administration of calcium can be safe for hyperkalemia in the setting of digoxin toxicity.²⁵ Unequivocally, however, the best treatment of hyperkalemia due to acute digoxin toxicity is Fab fragments. The treatment of hyperkalemia in the setting of chronic digoxin toxicity and renal failure is less clear; however, the evidence that calcium salts will be harmful is dubious at best. Calcium salts should be administered during several minutes through a secure peripheral intravenous site or through a central venous catheter. Indications are identical to those for hyperkalemia, including but not exclusive to a widened QRS duration on the electrocardiogram. A reasonable starting dose would be 3 g of calcium gluconate or 1 g of calcium chloride. Calcium salts should be followed immediately with other pharmacologic measures to lower serum potassium concentration.

Many patients receiving diuretic therapy are also magnesium depleted, even when the measured serum magnesium level is normal. If significant magnesium depletion is suspected (e.g., if electrocardiographic changes such as QTc prolongation are present), 1 to 2 g of magnesium sulfate can be given during 10 to 20 minutes (child: 25 mg/kg), followed by a constant infusion of 1 to 2 g/hr. Patients should be closely monitored for respiratory depression, which is usually preceded by progressive loss of deep tendon reflexes. Hypermagnesemia can exacerbate digitalis toxicity, but magnesium has been reported to reverse digoxin-induced tachydysrhythmias.²⁶ It is prudent to infuse magnesium slowly and to stop the infusion if heart block or bradycardia develops. Avoid magnesium in patients with renal failure. The role of magnesium in bradydysrhythmias and conduction blocks is less clear but probably dangerous because hypermagnesemia can impair impulse formation and AV conduction.

Atropine

Atropine is generally used for severe bradycardia and advanced AV block, with mixed results. Standard dosing (0.02 mg/kg in children with a minimum of 0.1 mg; 1 mg IV in adults) should be used. In general, an external or transvenous pacemaker should be readied when bradycardia or AV block appears.

Pacing

Transvenous pacing has been a mainstay of treatment for several decades, but the catheter may induce ventricular tachydysrhythmias in a myocardium made irritable by digoxin. Iatrogenic accidents of cardiac pacing are frequent (14 of 39, 36%) and often fatal (5 of 39, 13%).²⁷ We recommend avoidance of transvenous pacing unless external pacing fails. Pacing usually is required only temporarily while waiting for Fab fragments to take effect. Cardioversion for tachydysrhythmia also may be hazardous in the setting of digoxin intoxication. If it is deemed necessary, such as when the tachydysrhythmia is thought to be causing severe hypotension, we recommend use of lower than usual energy settings, such as 25 to 50 J, although there is no proof that this is less hazardous.

Signs and symptoms in children with digoxin poisoning are somewhat different (Table 152-2). Vomiting, somnolence, and obtundation are more common than in adults.¹⁸ CNS depression, in the absence of a history, might lead the clinician to suspect narcotic or sedative-hypnotic overdose or nontoxicologic causes, such as head injury, metabolic disorder, and CNS infection. Conduction disturbances and bradycardias are more common than ventricular dysrhythmias in children, especially with acute ingestion.^9,18

Table 152-2

Age Differences in Digitalis Intoxication

ADULT	PEDIATRIC
Toxic at lower levels	Asymptomatic at higher levels
Nausea, fatigue, and visual disturbances most common	Obtundation and vomiting more common than in adults
Tachydysrhythmias as common as blocks and bradydysrhythmias	Bradydysrhythmias and blocks most common
Allergic reactions to Fab fragments uncommon (<1%)	Allergic reactions extremely rare
V_d less variable (5-7.5 L/kg)	V_d more variable (3.5-6.0 L/kg in premature infants, 8.0-16.3 L/kg in infants 2-24 months)

Disposition

All patients who are symptomatic for digoxin toxicity with hyperkalemia, dysrhythmia, AV block, or significant comorbidity should be admitted to an intensive care unit or coronary care unit after treatment with Fab. Asymptomatic patients reporting an acute ingestion of a large quantity of digoxin should be admitted to an intensive care unit or coronary care unit for at least 12 hours of continuous cardiac monitoring to determine the need for Fab.

Beta-Adrenergic Blockers

Perspective

Beta-adrenergic blocking drugs became widely used in Europe in the 1960s for treatment of dysrhythmias. Their antihypertensive effects were later appreciated, and, by the 1970s, they were one of the most widely prescribed classes of drugs in the United States. Current indications include supraventricular dysrhythmias, hypertension (although the drugs have fallen out of favor for this indication), angina, thyrotoxicosis, migraine, and glaucoma. Of the numerous beta-blockers available, propranolol is the most deadly. In 2010, U.S. Poison Control Centers received more than 23,000 calls regarding beta-blocker exposures.¹

Principles of Disease

Pathophysiology

Beta-blockers structurally resemble isoproterenol, a pure beta-agonist. They competitively inhibit endogenous catecholamines such as epinephrine at beta-adrenergic receptors, blocking the catecholamine effects on augmentation of myocardial contraction (inotropy), enhancing cardiac conduction (dromotropy), and accelerating heart rate (chronotropy). These are all beta₁ effects. Complex beta₂ effects include vascular (smooth muscle relaxation and vasodilation), liver (glycogenolysis, gluconeogenesis), lung (bronchodilation), adipose tissue (release of free fatty acids), and uterus (smooth muscle relaxation) effects. Equally important properties, which vary from one beta-blocker to another, include cardioselectivity (beta₁ selectivity), membrane-stabilizing effect (fast cardiac sodium channel blocking properties), lipophilicity, and intrinsic sympathomimetic activity (Table 152-3). Although cardioselectivity is lost in overdose, cardioselective beta-blockers such as atenolol, metoprolol, and esmolol still have a lower mortality rate than that of propranolol.

Table 152-3

Selected Characteristics of Common Beta-Blockers

ISA, intrinsic sympathomimetic activity; MSE, membrane-stabilizing effect; VT, ventricular tachycardia.

Beta-blockers are rapidly absorbed after oral ingestion, and the peak effect of normal-release preparations occurs in 1 to 4 hours. Hepatic metabolism on first pass results in significantly less bioavailability after oral dosing than with intravenous injection (e.g., 1 : 40 for propranolol). Because volume of distribution for most beta-blockers generally exceeds 1 L/kg, hemodialysis is not efficacious for most beta-blockers. Protein binding varies from 0% for sotalol to 93% for propranolol. Elimination half-lives vary from 8 to 9 minutes for esmolol to as long as 24 hours for nadolol and others (see Table 152-3).

Clinical Features

The most common initial sign remains bradycardia, which should suggest the possibility of cardiac drug overdose. Hypotension and unconsciousness are the second and third most common signs (Box 152-8). Much of propranolol’s unique toxicity derives from its lipophilic nature, which allows it to penetrate the CNS, causing obtundation, respiratory depression, and seizures. Seizures probably result from a combination of hypotension, hypoglycemia, hypoxia, and direct CNS toxicity. Other beta-blockers are not lipophilic and do not have these effects. Surprisingly, bronchospasm is rarely a problem in cases of beta-blocker overdose, even with nonselective beta-blockers. The few cases of symptomatic bronchospasm respond to the usual bronchodilator nebulizations.

Propranolol, nadolol, betaxolol, and acebutolol have a membrane-stabilizing effect that impairs SA and AV node function and leads to bradycardia and AV block. Ventricular conduction is also depressed, leading to QRS widening, occasional ventricular dysrhythmias such as ventricular tachycardia and ventricular fibrillation, and cardiogenic shock. The intrinsic sympathomimetic activity of some beta-blockers, such as pindolol, oxprenolol, acebutolol, and carteolol, can lead to some unusual manifestations, such as ventricular dysrhythmias and sinus tachycardia instead of bradycardia. Labetalol and carvedilol also block alpha₁-adrenergic receptors, giving an additional mechanism for hypotension and distributive shock. However, labetalol’s beta-blockade is three (oral route) to seven (intravenous route) times more potent than its alpha-blockade. Nebivolol is a cardioselective beta-adrenergic blocker that also causes vasodilation through a unique mechanism: induction of endothelium-dependent vasodilation by stimulation of nitric oxide bioactivity.

In contrast to digitalis, beta-blocker toxicity has a more rapid onset; life-threatening CNS and cardiovascular effects can occur 30 minutes after oral overdose. Patients ingesting delayed-release preparations may remain asymptomatic for several hours, affording a valuable therapeutic window.

Diagnostic Strategies

Diagnosis and management depend entirely on the clinical picture. Blood levels of beta-blockers correlate poorly with severity of intoxication and are not readily available. Most urine toxicology screens do not identify antidysrhythmic drugs and are not helpful.²⁹ Hypoglycemia is common in children, and bedside determination of glucose concentration should be done if CNS depression is noted. Known access of the patient to a beta-blocker and consistent clinical features such as obtundation, seizures, hypotension, bradydysrhythmias, and occasionally tachydysrhythmias should lead the clinician to consider beta-blocker intoxication. Whereas some authors believe that a serum lactate concentration can help predict mortality in overdose patients,³⁰ this has not held true in pure beta-blocker ingestions.³¹

Differential Considerations

The combination of bradycardia and hypotension suggests beta-blockade or calcium channel blockade. Centrally acting alpha₂-adrenergic agonists, such as clonidine and tizanidine, or imidazolines, such as tetrahydrozoline and oxymetazoline, may also cause this constellation of symptoms. Without a history of beta-blocker ingestion, the diagnosis can be challenging, especially when noncardiac effects such as CNS depression and seizures predominate. Sodium channel poisoning with QRS widening can occur, suggesting other antidysrhythmic drugs or cyclic antidepressants. The differential diagnosis also includes sedative-hypnotic drug overdose, hypoglycemic drug ingestion, opiate overdose, CNS injury or infection, endocrine-metabolic disorder, sepsis, and acute myocardial infarction.

Management

Immediate measures include intravenous fluids, supplemental oxygen, and monitoring of cardiac rhythm and respirations. Activated charcoal has been used in the first hour after overdoses as a theoretic but unproven treatment, but theoretic advantages should be weighed against the very real risk of aspiration if obtundation or seizure ensues. Management of dysrhythmias and hypotension should not be delayed by administration of charcoal. Evidence for improved outcome is also lacking, but whole-bowel irrigation has been commonly used for sustained-release preparations with a polyethylene glycol solution (GoLYTELY), administered orally or by nasogastric tube at 2 L/hr in adults or 20 mL/kg initially in children. Again, risks and benefits make a clear recommendation impossible. Gastric lavage also carries procedural risks, and yet morbidity and mortality from beta-blockers are high and consideration of lavage in patients who present within 1 hour of ingestion is reasonable. With currently available evidence, gastric decontamination by activated charcoal, whole-bowel irrigation, or gastric lavage can neither be recommended nor criticized. Onset of toxicity is so uniformly early that absence of symptoms 4 hours after ingestion implies a low risk for subsequent morbidity unless a delayed-release preparation is involved.

Hypotension, Bradycardia, and Atrioventricular Block

The first step in the treatment of beta-blocker overdose is bolus administration of crystalloid fluids. In hypotensive patients, 20 to 40 mL/kg of normal saline or lactated Ringer’s solution can be infused and repeated. Atropine at standard doses may be used for bradycardia but is rarely effective. Infusion of more potent drugs or cardiac pacing is usually necessary. Atropine should be given before vagal stimuli, such as tracheal or gastric intubation. Early placement of a central venous catheter may be prudent as these patients frequently require central venous pressure monitoring, additional intravenous access, and administration of medications necessitating central access.

Calcium

Because the final common pathway for stimulation of adrenergic receptors is an increase in intracellular calcium concentration and deleterious effects on calcium transport may contribute to beta-blocker toxicity, intravenous administration of calcium has been suggested for treatment of hypotension. One gram of calcium gluconate contains 4.5 mEq of elemental calcium, whereas 1 g of calcium chloride contains 13.6 mEq of elemental calcium. Calcium chloride is an acidifying salt and can cause significant tissue damage and necrosis if extravasation occurs. Thus it should be administered through a central venous catheter or a secure large-bore antecubital peripheral line. Indications for calcium include hypotension and bradycardia. We recommend an initial dose of 13 to 25 mEq of calcium in adults (1-2 g calcium chloride, 3-6 g calcium gluconate) during 10 minutes. Patients in extremis may receive the initial dose during 1 minute. If a response is observed, repeated doses may be given every 20 minutes, or a constant infusion may be started at 0.5 mEq/kg/hr. It is prudent to raise the total serum calcium level no higher than 14 mg/dL, which the endocrine and oncology literature defines as the threshold of “severe” hypercalcemia; if ionized calcium is measured, we recommend not to exceed twice-normal levels. Children can receive 0.15 to 0.3 mEq/kg of calcium IV initially (10 to 30 mg/kg [0.1-0.3 mL/kg]) of 10% calcium chloride or 30-60 mg/kg calcium gluconate). The serum calcium level can be as high as 18.2 mg/dL within 15 minutes after a bolus of just 5 mL of 10% calcium chloride, so levels should be measured later during the constant infusion.

Glucagon

Because glucagon has both inotropic and chronotropic effects and does not depend on beta receptors for its action, it has long been used for beta-blocker toxicity. It stimulates the production of intracellular cyclic adenosine monophosphate independently of the beta-adrenergic receptor.³² Furthermore, it helps counteract the hypoglycemia induced by beta-blocker overdose. The dosing of glucagon is not well studied, but the drug is frequently used as a 5- to 10-mg IV bolus (0.05-0.1 mg/kg for children). If a response occurs to glucagon, the “response dose” should be started as an infusion at a rate of response dose during 1 hour. Glucagon has a very short (20-minute) half-life, and unfortunately its effect is often transient. Vomiting is a common complication of glucagon, so the airway should be secured or monitored closely to prevent aspiration. With cumulative large doses, glucagon should be diluted in 5% glucose in water for constant infusion. Side effects also include hypokalemia and allergic reactions. The response to glucagon alone is often inadequate, and glucagon is likely to be less effective than high-dose insulin.³³ Furthermore, hospitals may not be adequately stocked for treatment beyond a few hours.³⁴ From clinical experience, we find glucagon most useful as a transient therapy to bridge patients to high-dose insulin.

High-Dose Insulin

Despite glucagon’s longer history for treatment of beta-blocker toxicity, high-dose insulin (HDI) is probably a better agent. HDI is not a vasopressor; it is a profound inotrope ³⁵ with vasodilating properties.^36,37 The mechanism for HDI is not fully known, but it probably involves both optimization of the use of carbohydrates for fuel by cardiac myocytes and modulation of intracellular calcium.³⁸ HDI improves cardiac output significantly in beta-blocker toxicity from an increase in stroke volume more than heart rate. Dosing of HDI is not agreed on; dosing in humans successfully treated with HDI has ranged from 0.5 to 21.8 U/kg/hr.³⁹ In the largest human case series to date of patients receiving HDI for poison-induced cardiogenic shock, 11 of 12 patients survived; the only death occurred when HDI was terminated early because of a protocol violation.⁴⁰ Mean maximal HDI dosing in this series was 8.7 U/kg/hr. Previous recommendations for dosing of HDI were a bolus of 1 U/kg of regular insulin IV, followed by a drip at 1 U/kg/hr.⁴⁰ On the basis of animal data,⁴¹ some authors start HDI at 10 U/kg/hr in severely toxic patients with the belief that the glucose use from insulin saturates before the inotropic effect. Regardless of HDI dosing, patients should receive a bolus of dextrose before insulin and a dextrose infusion should be started thereafter, such as a bolus of 25 g glucose (1 traditional “amp” of D50) if the serum glucose concentration is below 200 mg/dL (11.1 mmol/L), followed by concentrated dextrose solutions (such as D25, D50, or even D70) through a central line because patients receiving HDI therapy are at risk of fluid overload. Glucose concentration should be monitored as frequently as every 10 minutes until a steady state of glucose use is achieved. Potassium concentration should also be monitored closely and potassium replaced as needed because patients may become hypokalemic.⁴⁰

Sodium Bicarbonate

Sodium channel blockade from beta-blockers with membrane-stabilizing activity, such as propranolol, occasionally causes QRS widening, which should respond to sodium bicarbonate. Bicarbonate should be dosed at 1 to 2 mmol/kg IV as a bolus repeated every 3 to 5 minutes until the QRS narrows.

Vasopressors and Other Inotropes

If hypotension or bradycardia persists, other cardioactive drugs are indicated. The use of vasopressors is not without risk; HDI is probably safer.³⁷ Vasopressors may be useful to transiently maintain mean arterial pressure (MAP) high enough to ensure adequate cerebral perfusion pressure (CPP). A MAP of 65 mm Hg is often quoted as the minimum MAP required to ensure adequate CPP.⁴² If the patient is not intubated and has a normal mental status, lower MAP readings are probably adequate. The more difficult situation of an intubated patient with a MAP slightly below 65 mm Hg represents a clinical dilemma. It is our practice to accept an MAP of 60 mm Hg if all other signs point to adequate organ perfusion.

A single drug of choice after HDI and glucagon has not emerged, but some clinicians favor isoproterenol (isoprenaline in Europe), dopamine, or epinephrine.²⁸ Other catecholamines that have been successfully used include norepinephrine, dobutamine, and phenylephrine. Often, norepinephrine or dopamine is added to beta-agonists such as isoproterenol that lack vasopressor activity. In the selection of cardioactive medications to supplement HDI and glucagon, we recommend early assessment of systemic vascular resistance and cardiac output by either indirect measurements with a pulse contour analysis–based hemodynamic monitoring tool such as the FloTrac device (Edwards Lifesciences; Irvine, Calif.) or Swan-Ganz catheter and choosing of appropriate drugs if either cardiogenic (inotropic drugs such as norepinephrine, dobutamine, dopamine) or distributive shock (pressors such as norepinephrine, phenylephrine, vasopressin) exists. Refractory cases of bradycardia may respond to an external or transvenous pacemaker. A pacemaker is particularly useful when the heart rate is the predominant cause of decreased cardiac output.

Intravenous Fat Emulsion (Intralipid)

Intravenous fat emulsion (IFE) is a promising new therapy for poison-induced cardiogenic shock. This therapy was first described for treatment of toxicity from local anesthetics such as bupivacaine.⁴³ IFE is proposed to work by three separate mechanisms: (1) the lipid sink, (2) modulation of intracellular metabolism, and (3) activation of ion channels.⁴⁴ The lipid sink theory posits that fat-soluble drugs are soaked up and removed from the site of toxicity, effectively increasing the volume of distribution for a fat-soluble drug. This is the predominant theory behind the use of IFE. A second theory involves optimization of cardiac metabolism. The heart under physiologic circumstances prefers free fatty acids; in times of stress it switches to glucose metabolism for energy. A dose of IFE theoretically provides a large supply of free fatty acids to optimize energy use in the heart. The final proposed mechanism involves direct activation of cardiac calcium channels. Animal evidence exists to support the use of IFE for both lipid-soluble beta-blockers (such as propranolol)⁴⁵ and non–lipid-soluble beta-blockers (such as atenolol).⁴⁶ Dramatic human case reports of successful resuscitations exist for propranolol,⁴⁷ nebivolol,³⁹ and metoprolol.⁴⁸ Although IFE was originally indicated for patients in cardiac arrest only, in 2011 the American College of Medical Toxicology released a position statement stating that “in circumstances where there is serious hemodynamic, or other, instability from a xenobiotic with a high degree of lipid solubility, lipid resuscitation therapy (IFE) is viewed as a reasonable consideration for therapy, even if the patient is not in cardiac arrest.”⁴⁹ Dosing for IFE is not agreed on. We recommend an initial bolus of 1.5 mL/kg of 20% lipid solution given during 2 to 3 minutes, followed immediately by an infusion of 0.25 mL/kg/min.⁴⁹ The bolus can be repeated up to two additional times for refractory patients. Response is typically within minutes of the bolus. We use IFE in patients with persistent bradycardia or hypotension not responding to intravenous fluids, calcium, and HDI.

Ventricular Dysrhythmias

Although it is uncharacteristic, ventricular tachydysrhythmias do occur sometimes. Cardioversion and defibrillation are indicated for ventricular tachycardia and ventricular fibrillation, respectively, following American Heart Association guidelines. Pulsatile ventricular tachycardia or frequent ventricular ectopy can most safely be treated with lidocaine. Other antidysrhythmic drugs, especially of classes IA and IC, should be avoided; they may potentiate AV block or be prodysrhythmic because of an additive membrane-stabilizing effect. Sotalol, unlike other beta-blockers, has class III as well as class II effects; that is, it prolongs the QT interval and can cause torsades de pointes and other ventricular dysrhythmias. Overdrive pacing with isoproterenol or a pacemaker and magnesium sulfate are specific therapies for torsades de pointes.

Extracorporeal Elimination and Circulatory Assistance

Hemodialysis or hemoperfusion may be beneficial for atenolol, acebutolol, nadolol, sotalol, and timolol, the beta-blockers with lower V_d, lower protein binding, and greater hydrophilicity.⁵⁰

Unlike overdoses of acetaminophen and iron, overdoses of cardiovascular drugs do not destroy tissue, and if circulation can be supported, complete recovery can be expected. An intra-aortic balloon pump or cardiopulmonary bypass can be lifesaving in cases of refractory hypotension.51,52 A percutaneous left ventricular assist device, although it has not been studied in beta-blocker toxicity, may also be useful. The relatively short half-lives (hours rather than days) of beta-blocking and calcium-blocking drugs fall within the temporal range of such interventions. To be successful, such heroic measures should be taken before prolonged hypotension leads to multiorgan ischemic injury (Box 152-9). Because most patients recover with just supportive care, these expensive and invasive interventions should be reserved for drugs and circumstances, such as propranolol, verapamil, and mixed cardiotoxic overdoses, that are associated with higher rates of mortality.

Pediatric Considerations

Severe pediatric beta-blocker poisonings are rare. In the cases reported, CNS, cardiac, and metabolic toxicities are similar.⁵³ Symptomatic hypoglycemia, however, is much more common in children and occurs even after therapeutic doses. Therefore, serum glucose concentration should be measured in children. Risk factors include young age, fasting state, and diabetes mellitus. Obtunded children should receive empirical glucose, 1 to 2 mL/kg of 25% glucose IV. In general, 5% glucose infusions have been sufficient to maintain euglycemia, especially with concomitant use of glucagon and catecholamines, which stimulate glucose release. Because glycogen mobilization is a beta₂ effect, hypoglycemia may be less common with the cardioselective (beta₁) blockers.

Seizures also occur in cases of pediatric beta-blocker overdose, but hypoglycemia is probably an important contributing factor. They are more common with the lipid-soluble beta-blockers propranolol and oxprenolol. Benzodiazepines are generally effective.

Children generally fare well after beta-blocker ingestion, with symptoms in only 8 of 378 (2%) potential beta-blocker exposures in children.⁵⁰

Disposition

Patients who remain completely asymptomatic for 6 hours after an oral overdose of normal-release preparations can be safely referred for psychiatric evaluation, with medical consultation for the first 24 hours. Patients ingesting sustained-release preparations should be admitted to a monitored bed, but those who remain asymptomatic 8 hours after ingestion are very unlikely to have toxicity. Those who have been hypotensive, who have more than first-degree heart block, or who have hemodynamically significant dysrhythmias should be admitted to an intensive care unit.

Calcium Channel Blockers

Perspective

Verapamil and nifedipine, the earliest calcium channel antagonists, were introduced in Europe in the 1970s and in the United States in the early 1980s. Calcium antagonists have found many clinical applications: angina pectoris, hypertension, supraventricular dysrhythmias, hypertrophic cardiomyopathy, and migraine prophylaxis. Most fatalities occur with verapamil, but severe toxicity and death have been reported for most drugs of this class. In 2010, U.S. Poison Control Centers received more than 10,000 calls about calcium channel blockers.¹

Pathophysiology

Calcium channel antagonists block the slow L-type calcium channels in the myocardium and vascular smooth muscle, leading to coronary and peripheral vasodilation. They also reduce cardiac contractility, depress SA nodal activity, and slow AV conduction. In cases of overdose, verapamil has the deadliest profile, combining severe myocardial depression and peripheral vasodilation. Both verapamil and diltiazem act on the heart and blood vessels, whereas dihydropyridines such as nifedipine cause primarily vasodilation and subsequent reflex tachycardia. As with beta-blockers, selectivity is lost after overdose, and toxicity is fourfold; the calcium antagonists have negative effects on heart rate, contractility, conduction, and vascular tone, with the exception of dihydropyridines, which tend to result in tachycardia even in severe toxicity.⁵⁴

All calcium channel blockers are rapidly absorbed, although first-pass hepatic metabolism significantly reduces bioavailability (Table 152-4). Onset of action and toxicity ranges from less than 30 minutes to 60 minutes. Peak effect of nifedipine can occur as early as 20 minutes after ingestion, but peak effect of sustained-release verapamil can be delayed for many hours. High protein binding and V_d greater than 1 to 2 L/kg make hemodialysis or hemoperfusion ineffective. Fortunately (except with sustained-release preparations), their half-lives are relatively short, limiting toxicity to 24 to 36 hours.

Table 152-4

Selected Characteristics of Some Calcium Channel Blockers