65: Cardioactive Steroids

The Ebers Papyrus provides evidence that the Egyptians used plants containing cardioactive steroids (CASs) at least 3000 years ago. However, it was not until 1785, when William Withering wrote the first systemic account about the effects of the foxglove plant, that the use of CASs was more widely accepted into the Western apothecary. Foxglove, the most common source of plant CAS, was initially used as a diuretic and for the treatment of “dropsy” (edema), and Withering eloquently described its “power over the motion of the heart, to a degree yet unobserved in any other medicine.”¹²⁴

Subsequently, CASs became the mainstay of treatment for congestive heart failure and to control the ventricular response rate in atrial tachydysrhythmias. Because of their narrow therapeutic index and widespread use, both acute and chronic toxicities remain important problems.⁸⁴ According to the American Association of Poison Control Centers data, between the years 2006 and 2011, there were approximately 8000 exposures to CAS-containing plants with one attributable deaths and about 14,500 exposures to CAS-containing xenobiotics resulting in more than100 deaths (Chap. 136).

Pharmaceutically induced CAS toxicity is typically encountered in the United States from digoxin; other internationally available but much less commonly used preparations are digitoxin, ouabain, lanatoside C, deslanoside, and gitalin. Digoxin toxicity most commonly occurs in patients at the extremes of age or those with chronic kidney disease (CKD). In children, most acute overdoses are unintentional by mistakenly ingesting an adult’s medication, or iatrogenic resulting from decimal point dosing errors (digoxin is prescribed in submilligrams, inviting 10-fold dosing calculation errors), or the elderly who are at risk for digoxin toxicity, most commonly from interactions with another medication in their chronic regimen or indirectly as a consequence of an alteration in the absorption or elimination kinetics. These include drug–drug interactions from an adult’s polypharmacy or from additional acute care xenobiotics that change CAS clearance in the liver or kidney, may alter protein binding and may result in increased bioavailability.

CAS toxicity may also result from exposure to certain plants or animals, including oleander (Nerium oleander), yellow oleander (Thevetia peruviana), which has been implicated in the suicidal deaths of thousands of patients in Southeast Asia,²⁶ foxglove (Digitalis spp), lily of the valley (Convallaria majalis), dogbane (Apocynum cannabinum), and red squill (Urginea maritima). CAS poisoning may result from teas containing seeds of these plants and water and herbal products contaminated with plant CASs (Chap. 45).^{16,19,52,79,90,97,116} Toxicity has resulted from ingestion, instead of the intended topical application, of a purported aphrodisiac derived from the dried secretion of toads from the Bufo species, which contains a bufadienolide-class CAS.^10,12,13 Although there have been no reported human exposures, fireflies of the Photinus species (P. ignitus, P. marginellus, and P. pyralis) contain the CAS lucibufagin that is structurally a bufadienolides (see Chemistry).^30,65

Cardioactive steroids contain an aglycone or “genin” nucleus structure with a steroid core and an unsaturated lactone ring attached at C-17. Cardioactive glycosides contain additional sugar groups attached to C-3. The sugar residues confer increased water solubility and enhance the ability of the molecule to enter cells. Cardenolides are primarily plant-derived aglycons with a five-membered unsaturated lactone ring. The bufadienolide and lucibufagin groups of CAS molecules are mainly animal derived and contain a six-membered unsaturated lactone ring (a plant derived exception is scillaren from red squill). Thus when the aglycone digoxigenin is linked to one or more hydrophilic sugar (digitoxoses) moieties at C-3, it forms digoxin, a cardiac glycoside. The aglycone of digitoxin differs from that of digoxin by the absence of a hydroxyl group on C-12, and ouabain differs from digoxin by both the absence of a hydroxyl group on C-12 and the addition of hydroxyl groups on C-1, C-5, C-10, and C-11. The cardioactive components in toad secretions are genins and lack sugar moieties.

The correlation between clinical effects and serum concentrations is based on steady-state concentrations, which are dependent on absorption, distribution, and elimination (Table 65–1). Although not proven, other CASs likely follow the absorption and distribution pattern of digoxin or digitoxin such that obtaining a serum concentration before 6 hours after ingestion (the time at which tissue concentrations plateau) gives a misleadingly high (predistribution) serum concentration. After therapeutic dosing, the intravascular distribution and elimination of digoxin from the plasma are best described using a two-compartment model that is achieved over approximately 36 to 48 hours in patients with normal kidney function. The distribution or α-phase represents the decrease in intravascular drug concentration and is dependent on whether the route of exposure was intravenous (IV) or oral (PO). Blood concentrations decline exponentially with a distribution half-life of 30 minutes as the drug moves from the blood to the peripheral tissues. Most of the intravascular CAS leaves the blood and distributes to the tissues, resulting in a large volume of distribution (Vd) (eg, the Vd of digoxin is 5–7 L/kg with therapeutic use). The β or elimination phase for digoxin has a half-life of approximately 36 hours and represents the total-body clearance of the drug, which is achieved primarily by the kidneys (70% of its clearance in a person with normal kidney function).^17,46

After a massive acute digoxin overdose, the apparent half-life may be shortened to as little as 13 to 15 hours because elevated serum concentrations result in greater renal clearance before distribution to the tissues.^51,111 Even with therapeutic administration of CAS, adjustments to the dosing regimen must be made to avert toxicity caused by the physiologic changes associated with aging, including hypothyroidism, chronic hypoxemia with alkalosis, and decreased glomerular filtration rate (GFR). Physiologic changes in CAS kinetics occur with functional decline of the liver, kidney, and heart and dynamics with electrolyte abnormalities, including hypomagnesemia, hypercalcemia, hypernatremia, and commonly hypokalemia. Therefore, serum concentrations should be monitored to avoid inadvertent toxicity. Hypokalemia resulting from a variety of mechanisms, such as the use of loop diuretics, poor dietary intake, diarrhea, and the administration of potassium-binding resins, enhances the effects of CASs on the myocardium and is associated with toxicity at lower serum CAS concentrations. Chronic hypokalemia reduces the number of Na⁺-K⁺-adenosine triphosphatase (ATPase) units in skeletal muscle, which may also alter drug effects.⁶³

Drug interactions between digoxin and quinidine, verapamil, diltiazem, carvedilol, amiodarone, and spironolactone are common.^{20,23,45,68,93} These interactions occur because of a reduction in the protein binding of the CAS, increasing availability to the tissues; a reduction in excretion as a consequence of a decrease in renal perfusion; or, as a result of interference with secretion by the kidneys and intestines, because of inactivation of P-glycoproteins. Also, in approximately 10% to 15% of patients receiving digoxin, a significant amount of digoxin is inactivated in the gastrointestinal (GI) tract by enteric bacterium, primarily Eubacterium lentum. Inhibition of this inactivation by the alteration of the GI flora by many antibiotics, particularly macrolides, results in increased bioavailability⁷³ and increased serum CAS concentrations.⁹²

Electrophysiologic Effects on Inotropy

It is currently believed that CASs increases the force of contraction of the heart (positive inotropic effect) by increasing cytosolic Ca²⁺ during systole. Both Na⁺ and Ca²⁺ ions enter and exit cardiac muscle cells during each cycle of depolarization and contraction–repolarization and relaxation. Sodium entry heralds the start of the action potential (phase 0) and carries the inward, depolarizing positive charge. Calcium subsequently enters the cardiac myocyte through L-type calcium channels during late phase 0 and the plateau phase of the action potential, and this Ca²⁺ entry triggers the release of Ca²⁺ into the cytosol from the sarcoplasmic reticulum. During repolarization and relaxation (diastole), Ca²⁺ is both pumped back into the sarcoplasmic reticulum by a local Ca²⁺-ATPase and is moved extracellularly by an Na⁺-Ca²⁺ antiporter (Fig. 65–1; Chap. 17).⁷⁸

CASs inhibit active transport of Na⁺ and K⁺ across the cell membrane during repolarization by binding to a specific site on the extracellular face of the α-subunit of the membrane Na⁺-K⁺-ATPase. This inhibits the cellular Na⁺ pump activity, which decreases Na⁺ extrusion and increases Na⁺ in the cytosol, thereby decreasing the transmembrane Na⁺ gradient. Because the Na⁺-Ca²⁺ antiporter derives its power not from adenosine triphosphate (ATP) but rather from the Na⁺ gradient generated by the Na⁺-K⁺ transport mechanism (the antiporter extrudes 1 calcium ion from the cell in exchange for 3 sodium ions moving into the cell down a concentration gradient),²⁹ the dysfunction of the Na⁺-K⁺-ATPase pump reduces Ca²⁺ extrusion from the cell. The additional cytoplasmic Ca²⁺ enhances the Ca²⁺-induced Ca²⁺ release from the sarcoplasmic reticulum during systole and by this mechanism increases the force of contraction of the cardiac muscle. Additional mechanisms of action are being explored and include creation of transmembrane calcium channels by cardioactive glycosides.¹

Effects on Cardiac Electrophysiology

At therapeutic serum concentrations, CASs increase automaticity and shorten the repolarization intervals of the atria and ventricles (Table 65–2). There is a concurrent decrease in the rate of depolarization and conduction through the sinoatrial (SA) and atrioventricular (AV) nodes, respectively. This is mediated both indirectly via an enhancement in vagally mediated parasympathetic tone and directly by depression of myocardial tissue. These changes in nodal conduction are reflected on electrocardiography (ECG) by a decrease in ventricular response rate to suprajunctional rhythms and by PR interval prolongation (the latter is part of digitalis effect). The effects of CASs on ventricular repolarization are related to the elevated intracellular resting potential caused by the enhanced availability of Ca²⁺ that manifests on the ECG as QT interval shortening and ST segment and T-wave forces opposite in direction to the major QRS forces. The last effect results in the characteristic scooping of the ST segments (referred to as the digitalis effect; Fig. 65–2).

Excessive increases in intracellular Ca²⁺ caused by CAS toxicity result in delayed after-depolarizations. These are fluxes in membrane potential caused by spontaneous Ca²⁺-induced Ca²⁺ release, which is caused by the excess intracellular Ca²⁺ and appear on the ECG as U waves. Occasionally, these may initiate a cellular depolarization that manifests as a premature ventricular contraction (Chap. 16).^28,60

Hypokalemia inhibits Na⁺-K⁺-ATPase activity and contributes to the pump inhibition induced by CASs, enhances myocardial automaticity, and increases myocardial susceptibility to CAS-related dysrhythmias. This may be partly a result of decreased competitive inhibition between the CAS and potassium at the Na⁺-K⁺-ATPase exchanger.⁹⁵ Severe hypokalemia (< 2.5 mEq/L) reduces the efficacy of sodium-potassium pump function, slowing the pump and exacerbating concomitant Na⁺–K⁺ pump inhibition by CASs.⁶⁰

Effects of Cardioactive Steroids on the Autonomic Nervous System

CASs affect the parasympathetic system by increasing the release of acetylcholine from vagal fibers,^75,114 possibly through augmentation of intracellular Ca²⁺. CASs affect the sympathetic system by increasing efferent sympathetic discharge,^85,109 which may exacerbate dysrhythmias.

Although there are differences in the signs and symptoms of acute versus chronic CAS poisoning, adults and children have similar manifestations when poisoned.

Noncardiac Manifestations

Acute Toxicity.

An asymptomatic period of several minutes to several hours may follow a single administered toxic dose of CAS. The first effects are typically nausea, vomiting, or abdominal pain. Central nervous system effects of acute toxicity may include lethargy, confusion, and weakness that are not caused by hemodynamic changes.¹⁶ The absence of nausea and ­vomiting within several hours following exposure makes severe acute CAS poisoning unlikely.

Chronic Toxicity.

Chronic toxicity is often difficult to diagnose as a result of its insidious development and protean manifestations, including weakness, anhedonia, and loss of appetite. Symptoms may also include those that occur with acute poisonings; however, they are often less obvious. GI findings include anorexia, nausea, vomiting, abdominal pain, and weight loss. Neuropsychiatric disorders include delirium, confusion, drowsiness, headache, hallucinations, and, rarely, seizures.^16,38,40 Visual disturbances include transient amblyopia, photophobia, blurring, scotomata, photopsia, decreased visual activity, and aberrations of color vision (chromatopsia), such as yellow halos (xanthopsia) around lights.^69,70

Electrolyte Abnormalities.

Elevated serum potassium concentrations frequently occur in patients with acute CAS poisoning.^60,63 Hyperkalemia has important prognostic implications because the serum potassium concentration is a better predictor of lethality than either the initial ECG changes or the serum CAS concentration.^5,6 In a study of 91 acutely digitoxin poisoned patients conducted before digoxin-specific Fab was available, approximately 50% of the patients with serum potassium concentrations of 5.0 to 5.5 mEq/L died. Although a serum potassium concentration lower than 5.0 mEq/L was associated with no deaths, all 10 patients with serum potassium concentrations above 5.5 mEq/L died.⁵ Elevation of the serum potassium concentration after administration of CASs is a result of CAS inhibition of the Na⁺-K⁺-ATPase pump, which results in the inhibition of potassium uptake in exchange for Na⁺ by skeletal muscle (the largest potassium reservoir). Hyperkalemia probably causes further hyperpolarization of myocardial conduction tissue, increasing AV nodal block, thereby exacerbating CAS-induced bradydysrhythmias and conduction delays.⁶⁰ However, correction of the hyperkalemia alone does not increase patient survival⁵; it is a marker for, but not the cause of, the morbidity and mortality associated with CAS poisoning. Hyperkalemia may also be marker of increased morbidity and subsequent mortality with chronic digoxin overdose.¹²⁶ The interrelationships between intracellular and extracellular potassium and CAS therapy are complex and incompletely understood.

Cardiac Manifestations

General.

With therapeutic use, CASs slow tachydysrhythmias without causing hypotension. With poisoning, the alterations in cardiac rate and rhythm may result in nearly any dysrhythmia with the exception of a rapidly conducted supraventricular tachydysrhythmia due to the prominent AV nodal depressive effect of CASs. In 10% to 15% of cases, the first sign of toxicity is the appearance of an ectopic ventricular rhythm.⁹⁴ Although no single dysrhythmia is pathognomonic of CAS toxicity, toxicity should be suspected when there is evidence of increased automaticity in combination with impaired conduction through the SA and AV nodes.⁶⁰ Bidirectional ventricular tachycardia is nearly diagnostic, although it may also occur with poisoning by aconitine and other uncommon xenobiotics¹⁰⁵ (Fig. 16–19). Dysrhythmias, including atrial tachycardia with high-degree AV block, result from the complex electrophysiologic influences on both the myocardium and conduction system of the heart that stem from direct, vagotonic, and other autonomic actions of the CASs.

The effects of digoxin vary with dose and the type of cardiac tissue involved. The atrial and ventricular myocardial tissues exhibit increased automaticity and excitability, resulting in tachydysrhythmias and extrasystoles. In atrial and nodal conducting system tissues, signal velocity is reduced, resulting in an increased PR interval and AV nodal block. AV junctional blocks of varying degrees associated with increased ventricular automaticity are the most common cardiac manifestations, occurring in 30% to 40% of patients with CAS toxicity.⁷⁶ AV dissociation may result from suppression of the dominant pacemaker with escape of a secondary pacemaker or from inappropriate acceleration of a ventricular pacemaker. Hypotension, shock, and cardiovascular collapse may ensue. Table 65–3 summarizes these findings.

Acute Toxicity.

Many cardiac dysrhythmias are associated with CAS toxicity. These dysrhythmias are unified by a sensitized myocardium and a depressed AV node (Table 65–3). The initial bradydysrhythmia results from increased vagal tone at the SA and AV nodes and is often responsive to atropine.

Chronic Toxicity.

Bradydysrhythmias that appear later in acute poisonings and with chronic CAS toxicity occur by direct actions on the heart and often are minimally responsive to atropine, if at all. Ventricular tachydysrhythmias are more common in patients with chronic or late acute poisoning.

Properly obtained and interpreted serum digoxin concentrations aid significantly in the management of patients with suspected digoxin toxicity, as well as in the management of patients poisoned by several other CAS. Although most institutions report a therapeutic range for serum digoxin concentration from 0.5 to 2.0 ng/mL (SI units, 1.0–2.6 nmol/mL), current understanding suggests lowering the upper limit to 1.0 ng/mL maintains benefit while decreasing the risk of toxicity.^98,107 In addition to determining a serum CAS concentration, care must be taken to interpret the concentration as a correlate with the clinical condition of the patient; the interval between the last dose and the time the blood sample was taken; and the presence of other metabolic abnormalities, including hypokalemia, hypomagnesemia, hypercalcemia, hypernatremia, alkalosis, hypothyroidism, and hypoxemia, and the use of xenobiotics such as amiodarone, calcium channel blockers, catecholamines, quinidine, and diuretics.

CAS poisoning is multifactorial and using the upper limit of the therapeutic range of digoxin as the sole indicator of toxicity may be misleading,¹⁰¹ as there is an overlap in serum digoxin concentrations between toxic and nontoxic patients. In general, a patient’s clinical condition and serum concentration correlate well; the significance of a serum concentration depends on when the value is obtained after an acute ingestion to account for the distribution phase of the drug. Asymptomatic patients with CAS concentrations obtained prior to completion of the α distribution, found to be above the therapeutic range, are less often toxic but require close observation and retesting. Patients with mean pharmaceutical CAS serum concentrations above 2 ng/mL for digoxin and above 40 ng/mL for digitoxin measured 6 hours after the last dose often are clinically toxic.⁵⁹ A patient with a markedly elevated CAS concentration at any point after ingestion(eg, ≥ 15 mg/mL) requires definitive therapy.

In most hospitals, “digoxin levels” are the only estimation available to physicians in the acute setting when evaluating a patient for presumed non-digoxin CAS poisoning. The assays typically used in most institutions frequently, but unpredictably, cross-react with other plant- or animal-derived CASs. Although a monoclonal digoxin immunoassay accurately quantifies the serum digoxin concentration, an elevated digoxin concentration in the correct clinical setting may qualitatively assist in making a presumptive diagnosis of nondigoxin CAS exposure (Chaps. 45 and 121).^14,88 For example, using various techniques, including high-performance liquid chromatography and monoclonal and polyclonal antibody analysis, “digoxin” concentrations were determined from serum to which oleandrin and oleandrigenin from Nerium oleander was added or from patients exposed to Thevetia peruviana (yellow oleander) or toad-secreted bufadienolides.^10,26,54 Patients with CAS poisoning from plant- or animal-derived CASs may have a positive detection of CAS when using a polyclonal digoxin assay and a low or negative finding when using a monoclonal assay (Chaps. 45 and 121).

Serum concentrations of digoxin are measured in one of two ways: free digoxin and total digoxin. The most common method of quantifying total digoxin in the serum is by fluorescence polarization immunoassay. Under normal circumstances, measuring total digoxin in the serum is sufficient because serum concentrations are predictive of cardiac concentrations.²⁴ However, after the use of digoxin-specific Fab (which remains almost entirely within the intravascular space {Vd, 0.40 L/kg}), there is a large elevation in total CAS concentrations because the CAS is drawn from the tissues and complexes with the antibody fragment, thus trapping the CAS in the intravascular space. When this bulk movement is achieved by binding with Fab fragments, a tremendous increase in total serum digoxin concentrations occurs—representing free plus bound (inactivated) CAS. In this situation, requesting a “free digoxin level” will avoid this spurious increase and reflect clinically relevant unbound digoxin concentration. Paradoxically, excess digoxin Fab may cause a false elevation in digoxin concentration (Chap. 6).

Endogenous DigoxinLike Immunoreactive Substance

Some patients have a positive digoxin assay resulting from an endogenous digoxinlike immunoreactive substance (EDLIS) that is structurally and functionally similar to prescribed CASs.⁴⁵ This substance has been found in patients with increased inotropic need or reduced renal clearance, including neonates¹¹⁷, patients with endstage kidney disase,^11,41,53 liver disease,⁸¹ subarachnoid hemorrhage,¹²³ congestive heart failure,^39,102 insulin-­dependent diabetes,³⁵ stress,^40,118 acromegaly,²⁶ or hypothermia,¹¹⁷ after strenuous exercise¹¹⁸ and in pregnancy.^32,42,50 An endogenous Na⁺-K⁺-ATPase inhibiting dihydropyrone-substituted bufadienolide CAS has been isolated from human placenta.³³ It differs from the toad bufadienolides solely by a single double-bond pyrone ring. Because bufadienolides are not normally found in either healthy humans or edible plants, a synthetic pathway to produce dihydropyrone-substituted steroids in humans may be responsible for EDLIS. Further research is necessary to confirm this pathway.⁵⁰ The clinician suspecting this problem should consult the clinical laboratory.³⁴ Clinical observations indicate that the serum digoxin concentration contributed by EDLIS is usually less than 2 ng/mL. Other endogenous substances, such as bilirubin,⁸¹ and xenobiotics, such as spironolactone,¹⁰³ may also cross-react with the digoxin assay and cause a false-positive result.

Acute Management Overview

Initial treatment of a patient with acute CAS poisoning includes providing general care, (eg, GI decontamination, monitoring for dysrhythmias, measuring electrolyte and digoxin concentrations) and definitive care (eg, administering digoxin-specific antibody fragments). Secondary care includes treating complications such as dysrhythmias and electrolyte abnormalities.

Gastrointestinal Decontamination

The initial treatment should be directed toward prevention of further GI absorption. Rarely, if ever, should emesis or lavage may be considered because efficacy is limited due to rapid absorption from the gut and to the emetic effects of the drug itself. Patients with chronic ingestion also do not benefit from these GI decontamination techniques. Because many CASs, such as digitoxin and digoxin, are recirculated enterohepatically, both late and repeated activated charcoal administration (1 g/kg of body weight every 2–4 hours for up to 4 doses) are beneficial in reducing serum concentrations.^{17,21,67,71,86,121} Activated charcoal prevents reabsorption of CAS from the GI tract and reduces the serum half-life. It should be administered in CAS toxic patients if definitive therapy with digoxin-specific Fab is not immediately available or when renal function is inadequate.^21,

Advanced Management

Digoxin-Specific Antibody Fragments.

The definitive therapy for patients with life-threatening dysrhythmias from CAS toxicity (in descending order of associated mortality: ventricular tachycardia, AV junctional tachycardia, AV block¹²⁷) is to administer digoxin-specific antibody fragments.^{2,34,36,87,90,97,106,112,125} Purified digoxin-specific Fab causes a sharp decrease in free serum digoxin concentrations; a concomitant, but clinically unimportant, massive increase in total serum digoxin concentration; an increase in renal clearance of CAS (as a bound drug); and a decrease in the serum potassium concentration.² In addition, the administration of digoxin-specific Fab is pharmacoeconomically advantageous.²² Although the antidote itself is relatively expensive, its expense is far outweighed by obviating the need, risk, and expense of long-term intensive care unit stays and of repetitive evaluation of potassium and digoxin concentrations. Table 65–4 lists the indications for administering digoxin-specific Fab. Extensive discussion is found in Antidotes in Depth: A19.

Other Cardiac Therapeutics.

Secondary treatments used in patients with symptomatic CAS exposures include the use of atropine for supraventricular bradydysrhythmias or high degrees of AV block. Atropine dosing is 0.5 mg administered IV to an adult or 0.02 mg/kg with a minimum of 0.1 mg to a child. Atropine should be titrated to block the vagotonic effects of CASs. The dose may be repeated at 5-minute intervals if necessary. Therapeutic success is unpredictable because the depressant actions of CASs are mediated only partly through the vagus nerve.

Phenytoin and lidocaine are rarely used (secondary to Fab fragments obviating their utility) for the management of CAS-induced ventricular tachydysrhythmias and ventricular irritability. These xenobiotics depress the enhanced ventricular automaticity without significantly slowing, and perhaps enhancing, AV nodal conduction.⁹⁶ In fact, phenytoin may reverse digitalis-induced prolongation of AV nodal conduction while suppressing digitalis-induced ectopic tachydysrhythmia without diminishing myocardial contractile forces.⁴⁸ In addition, phenytoin may terminate supraventricular dysrhythmias induced by digitalis more effectively than lidocaine.⁹⁶ Underlying atrial fibrillation and flutter typically do not convert to a normal sinus rhythm with administration of phenytoin or lidocaine. When used, phenytoin should be slowly IV infused (~ 50 mg/min) or in boluses of 100 mg repeated every 5 minutes until control of the dysrhythmias is achieved or a maximum of 1000 mg has been given in adults or 15 to 20 mg/kg in children.^9,80 Fosphenytoin has not been evaluated in this setting. Maintenance PO doses of phenytoin (300–400 mg/day in adults and 6–10 mg/kg/day in children) should be continued until digoxin toxicity is resolved. Lidocaine is given as a 1- to 1.5-mg/kg IV bolus followed by continuous infusion at 1 to 4 mg/min in adults, or as a 1- to 1.5-mg/kg IV bolus followed by 30 to 50 μg/kg/min in children as required to control the rhythm disturbance (Chap. 64).

Class IA antidysrhythmics are contraindicated in the setting of CAS poisoning because they may induce or worsen AV nodal block and decrease His-Purkinje conduction at slow heart rates and because their α-adrenergic receptor blockade and vagal inhibition may induce significant hypotension and tachycardia. Class IA antidysrhythmics are also prodysrhythmogenic, and their safety in the setting of CAS poisoning is unstudied. Additionally, quinidine reduces renal clearance of digoxin and digitoxin. The use of isoproterenol should be avoided in CAS-induced conduction disturbances because there may be an increased incidence of ventricular ectopic activity in the presence of toxic concentrations of CAS.

Pacemakers and Cardioversion

External or transvenous pacemakers have had limited indications in the management of patients with CAS poisoning. In one retrospective study of 92 digitalis-poisoned patients, 51 patients were treated with cardiac pacing, digoxin-specific Fab, or both; the overall mortality rate was 13%.¹¹³ Prevention of life-threatening dysrhythmias failed in 8% of patients treated with immunotherapy and 23% of patients treated with internal pacemakers. The main reasons for failure of digoxin-specific Fab were pacing-induced dysrhythmias and delayed or insufficient doses of digoxin-specific Fab. Iatrogenic complications of pacing occurred in 36% of patients. Thus, overdrive suppression with a temporary transvenous pacemaker should not be used in the presence of CAS poisoning.^6,113 In the setting of digoxin poisoning, administration of transthoracic electrical cardioversion for atrial tachydysrhythmias is associated with the development of potentially lethal ventricular dysrhythmias. The dysrhythmias were related to the degree of toxicity and the amount of administered current in cardioversion.⁹⁹ Transthoracic pacing may be attempted for atropine unresponsive bradydysrhythmias in settings where definitive care (digoxin-specific Fab fragments) are delayed or unavailable. In CAS-poisoned patients with unstable rhythms, such as unstable ventricular tachycardia or ventricular fibrillation, cardioversion, and defibrillation, respectively, are indicated.

Electrolyte Therapy

Potassium.

Hypokalemia and hyperkalemia may exacerbate CAS cardiotoxicity even at “therapeutic” digoxin concentrations. When hypokalemia is noted in conjunction with tachydysrhythmias or bradydysrhythmias, potassium replacement should be administered with serial monitoring of the serum potassium concentration. Digoxin-specific Fab administration generally should be withheld until the hypokalemia is corrected as the life-threatening manifestations of CAS cardiotoxicity may resolve.

Hyperkalemia may also exacerbate CAS-induced cardiotoxicity, at “therapeutic” digoxin concentrations. Reduction in potassium concentrations should be judiciously initiated with care to avoid hypokalemia. Any exacerbation of CAS cardiotoxicity despite this correction should be treated immediately with Fab fragments.

In acute CAS toxicity, if potassium is at least 5 mEq/L, digoxin-specific antibody fragments are indicated. If digoxin-specific Fab is not available immediately, and ECG evidence of a dysrhythmia suggestions of hyperkalemia is present, an attempt should be made to lower the serum potassium with IV insulin, dextrose, sodium bicarbonate, and PO administration of the ion-exchange resin sodium polystyrene sulfonate as indicated. Caution should be applied to the subsequent administration of digoxin-specific Fab because of concern for profound hypokalemia.

Although calcium is beneficial in most hyperkalemic patients, in the setting of CAS poisoning, administration of calcium salts is considered to be potentially dangerous. A number of experimental studies cite the additive or synergistic actions of calcium and CAS on the heart (because intracellular hypercalcemia is already present), resulting in dysrhythmias,^37,83,104 cardiac dysfunction⁶¹ (eg, hypercontractility, so-called “stone heart,” hypocontractility), and cardiac arrest.^72,104,119 Although a 2004 study was unable to show an adverse effect,⁴³ there exist three case reports^8,64 of CAS-poisoned patients who died at various intervals after calcium administration, which supports the withholding of calcium administration in the setting of hyperkalemia induced by CAS poisoning.

The purported mechanism is augmented intracellular cytoplasmic Ca²⁺, which results from an increased transmembrane concentration gradient that further inhibits calcium extrusion through the Na⁺-Ca²⁺ exchange or increased intracytoplasmic stores.⁵⁹ This additional cytoplasmic calcium may result in altered contraction of myofibril organelles,⁶¹ less negative intracellular resting potential that allows delayed afterdepolarizations to reach firing threshold,^47,59,83 altered function of the sarcoplasmic reticulum,^61,95 or increased calcium interfering with myocardial mitochondrial function (Chaps. 16 and 17).⁶¹ Although some investigators suspect that the rate of administration of the calcium may be a factor in the subsequent cardiac toxicity,^72,83 calcium administration should be avoided because better, safer, alternative treatments, such as digoxin-specific Fab, insulin, and sodium bicarbonate, are available for CAS-induced hyperkalemia.^{8,37,64,83,104}

Magnesium.

Hypomagnesemia may also occur in CAS-poisoned patients secondary to the contributory factors mentioned with hypokalemia, such as long-term diuretic use to treat congestive heart failure. The theoretical benefits of magnesium therapy in the setting of hypomagnesemia include blockade of the transient inward calcium current, antagonism of calcium at intracellular binding sites, decreased CAS-related ventricular irritability, and blockade of potassium egress from CAS-poisoned cells.^{4,31,55,89,100,110,122} Although hypomagnesemia increases myocardial digoxin uptake and decreases cellular Na⁺-K⁺-ATPase activity, there is conflicting evidence as whether magnesium “reactivates” the CAS-bound Na⁺-K⁺-ATPase activity.^81,100,110

A common regimen uses 2 g of magnesium sulfate IV over 20 minutes in adults (25–50 mg/kg/dose to a maximum of 2 g in children). After stabilization, adult patients with severe hypomagnesemia may require a magnesium infusion of 1 to 2 g/h (25–50 mg/kg/h to a maximum of 2 g in children), with serial monitoring of serum magnesium concentrations, telemetry, respiratory rate (observing for bradypnea), deep tendon reflexes (observing for hyporeflexia), and monitoring of blood pressure. Magnesium is contraindicated in the setting of bradycardia or AV block, preexisting hypermagnesemia, and renal insufficiency or failure.

Extracorporal Removal of Cardioactive Steroids

Forced diuresis,⁶⁶ hemoperfusion,^77,79,120 and hemodialysis¹²⁰ are ineffective in enhancing the elimination of digoxin because of its large volume of distribution (4–10 L/kg), which makes it relatively inaccessible to these techniques. Because of its high affinity for tissue proteins, approximately 10% of the amount of digoxin is found in the serum than is found at the tissue level, and of that amount, approximately 20% to 40% is protein bound.⁵⁷

• Digoxin and digitoxin are the most commonly prescribed members of the drugs classified as CASs and they have a narrow therapeutic index.

• Both cardiac and noncardiac effects occur after CAS poisoning, including nausea, vomiting, headache, weakness, altered mental status bradycardia, atrial and ventricular ectopy with block, or hyperkalemia.

• CAS overdose mimics include dysrhythmias from electrolyte abnormalities, primarily hypokalemia, or hypomagnesemia which can be corrected by repletion of potassium or magnesium.

• Definitive therapy for CAS poisoning is the early administration of digoxin-specific Fab immunotherapy coupled with both decontamination techniques including activated charcoal and supportive therapy.

Acknowledgment

Neal A. Lewin, MD, contributed to this chapter in previous editions.

References