INTRODUCTION — In 1785, Sir William Withering described the use of the foxglove plant, Digitalis purpurea, for treatment of heart failure [1]. More than 200 years later, cardiac glycosides are still prescribed for patients with atrial fibrillation and heart failure or left ventricular dysfunction.
While its use has declined, digoxin continues to account for significant morbidity and mortality [2]. In 2017, there were 1689 cases of cardiac glycoside exposures reported to United States poison control centers. Of these, 559 patients suffered moderate or major toxicity and 23 died [3].
In addition to digoxin, other cardiac glycosides exist and have been associated with toxicity. These include: the xenobiotics ouabain and lanatoside C; various plants, including foxglove, dogbane, red squill, lily of the valley, oleander, and henbane; and bufadienolides, cardioactive steroids found in the skin of toads belonging to the Bufonidae family [4]. In 2018, there were an additional 1566 cases of cardiac glycoside exposure reported to United States poison control centers from various plant species [3].
The pharmacology, diagnosis, and management of acute and chronic digoxin poisoning will be reviewed here. The dosing of digoxin-specific antibody (Fab) fragments for the treatment of digoxin toxicity and the therapeutic use of digoxin are discussed separately.
●(See "Dosing regimen for digoxin-specific antibody (Fab) fragments in patients with digoxin toxicity".)
●(See "Control of ventricular rate in atrial fibrillation: Pharmacologic therapy", section on 'Digoxin'.)
●(See "Treatment with digoxin: Initial dosing, monitoring, and dose modification".)
●(See "Secondary pharmacologic therapy in heart failure with reduced ejection fraction (HFrEF) in adults".)
PHARMACOLOGY AND CELLULAR TOXICOLOGY — Cardiac glycosides all possess a steroid nucleus with an unsaturated lactone at the C17 position, and at least one glycosidic residue at the C3 position (figure 1) [5]. Cardiac glycosides are used primarily to increase inotropy in cardiac myocytes but also affect cells in the vascular smooth muscle and sympathetic nervous system [5-7].
Normal depolarization of the cardiac myocyte begins with the opening of the fast sodium channels. The resulting increase in intracellular sodium, and subsequent change in the resting membrane potential, opens voltage-gated calcium channels. The initial influx of calcium induces further release of calcium from the sarcoplasmic reticulum, which results in muscle contraction [8]. Sodium is then removed from the cell by, among several mechanisms, the sodium-potassium-ATPase. Some calcium is removed from the cell by the sodium-calcium antiporter.
Cardiac glycosides reversibly inhibit the sodium-potassium-ATPase, causing an increase in intracellular sodium and a decrease in intracellular potassium [1,5]. The increase in intracellular sodium prevents the sodium-calcium antiporter from expelling calcium from the myocyte, which increases intracellular calcium. The net increase in intracellular calcium augments inotropy [5,9]. Cardiac glycosides also increase vagal tone, which results in decreased conduction through the sinoatrial and atrioventricular nodes [5].
Excessive intracellular calcium may cause delayed after-depolarizations, which may in turn lead to premature contractions and trigger dysrhythmias. Cardiac glycosides shorten repolarization of the atria and ventricles, decreasing the refractory period of the myocardium, thereby increasing automaticity and the risk for dysrhythmias [10,11].
The effects of cardiac glycosides on peripheral vasculature can vary [11-13]. In patients without heart failure, cardiac glycosides can increase vasoconstriction. However, in patients with advanced decompensated heart failure, digitalis has been shown to reduce plasma renin concentrations, causing peripheral vasodilation [11]. This difference is likely due to enhanced responsiveness of the baroreceptors in patients with chronic heart failure [12]. (See "Overview of the management of heart failure with reduced ejection fraction in adults".)
KINETICS — Digoxin is the only cardiac glycoside commonly used for medicinal purposes. Important pharmacokinetic properties of digoxin are summarized in the attached table (table 1).
Digoxin has a narrow therapeutic index and toxicity is common [14]. Furthermore, dosing adjustments must be made whenever significant alterations occur in factors affecting absorption, distribution, or elimination. Such factors are numerous and include changes in volume of distribution due to age or increased adipose stores, diminished protein binding from conditions causing hypoalbuminemia, and renal impairment resulting in decreased elimination.
Digoxin is a substrate of intestinal and renal p-glycoprotein. P-glycoprotein is an efflux pump that excretes many drugs into the intestine or proximal renal tubule, thereby lowering serum concentrations. Drugs that alter p-glycoprotein activity can increase serum digoxin concentrations [15,16]. Examples of such drugs include verapamil, diltiazem, quinidine, and amiodarone (table 2) [17,18].
The molecular weight of digoxin is large, making extracorporeal elimination ineffective. (See 'Extracorporeal removal' below.)
CLINICAL FEATURES AND DIAGNOSIS — Cardiac glycosides, both naturally occurring and from pharmaceutical sources, can cause toxicity. In addition to digoxin, other cardiac glycosides that have been associated with toxicity include: the xenobiotics ouabain and lanatoside C; various plants, including foxglove, dogbane, red squill, lily of the valley, oleander, and henbane; and bufadienolides, cardioactive steroids found in the skin of toads belonging to the Bufonidae family [4].
Critical clinical manifestations of toxicity are usually cardiac but may include gastrointestinal and neurologic signs. The diagnosis of cardiac glycoside toxicity is based upon clinical and electrocardiographic manifestations rather than isolated elevated serum digoxin concentrations. Furthermore, presentation can vary depending upon whether toxicity is acute or chronic.
History — Determine the agent, amount taken, time of ingestion, and any coingestants when possible. The time of ingestion or last dose is especially important for interpreting serum digoxin concentration. A level drawn prematurely, or fewer than six hours since ingestion, may be falsely elevated due to incomplete drug distribution. Determine if toxicity is acute or chronic by identifying if the patient normally takes digoxin therapeutically or if the patient ingested someone else's prescription. (See 'Serum digoxin concentration: Performance and interpretation' below.)
Ask about symptoms suggesting an acute illness, such as gastroenteritis, that may have caused dehydration or acute renal insufficiency and contributed to the development of chronic toxicity [19]. Inquire carefully about gastrointestinal, cardiac, and neurologic manifestations, including visual disturbances, which are all common findings associated with chronic toxicity.
Inquire also about symptoms that suggest hypoperfusion, such as confusion and abdominal pain, which may stem from mesenteric ischemia [20]. (See "Overview of intestinal ischemia in adults", section on 'Clinical features'.)
Obtain a thorough medication history to determine if any recent additions or dosing changes were made. Several medications, including verapamil, amiodarone, and quinidine, can increase serum digoxin concentrations (table 2). Ask if any medications were recently discontinued, as the discontinuation of a drug that decreases digoxin concentrations can cause digoxin to accumulate.
Physical examination — After initial evaluation of the patient's airway and breathing, the clinician should assess the patient's vital signs. Bradycardia is frequently encountered in cardiac glycoside toxicity.
Look for evidence of hypoperfusion and end organ dysfunction. Pay particular attention to mentation and neurologic status, keeping in mind that such effects are often due to direct toxicity but may be secondary to cerebral hypoperfusion. Look for symptoms and signs suggestive of acute mesenteric ischemia, which is a rare complication. (See "Overview of intestinal ischemia in adults", section on 'Physical examination'.)
Clinical manifestations — In both acute and chronic digoxin toxicity, cardiac effects are of the greatest concern. The cardiac manifestations of cardiac glycoside toxicity can include virtually any type of dysrhythmia with the exception of rapidly conducted atrial dysrhythmias [10]. Cardiac-glycoside-related dysrhythmias are discussed below and separately. (See 'Electrocardiogram' below and "Cardiac arrhythmias due to digoxin toxicity".)
Other symptoms of acute and chronic digoxin toxicity may overlap, but a few important differences should be noted. With an acute ingestion, the patient may remain asymptomatic for several hours then develop significant gastrointestinal symptoms, such as anorexia, nausea, vomiting, and abdominal pain. Neurologic manifestations such as confusion and weakness, independent of hemodynamic parameters, are common and often develop later upon distribution of the drug into the central nervous system. Electrolyte abnormalities occur with both acute and chronic toxicity and are discussed further below. (See 'Electrolyte abnormalities' below.)
Chronic toxicity is often more difficult to diagnose, as symptom onset tends to be more insidious and may occur over a period ranging from days to months. Gastrointestinal symptoms, such as anorexia, nausea, and vomiting, can occur but may be less pronounced. Neurologic manifestations, such as lethargy, fatigue, delirium, confusion, disorientation, and weakness, may be prominent in chronic toxicity [21]. Often patients are brought to medical attention by family members who note a change in mental status or cognition.
Visual changes associated with cardiac glycoside toxicity are varied and may include alterations in color vision (chromatopsia), diplopia, photophobia, decreased visual acuity, photopsia, scotomas, or blindness. Chromatopsia, specifically xanthopsia (objects appear yellow), is classically associated with cardiac glycoside toxicity but is frequently absent and not necessary for diagnosis.
LABORATORY AND ECG EVALUATION
Approach to testing — In the patient with suspected digoxin toxicity, the following studies should be obtained:
●Serum digoxin concentration:
For an acute overdose, obtain a serum concentration measurement on presentation and approximately six hours after the ingestion; for chronic toxicity, obtain a concentration on presentation and interpret it in the context of last administered dose (>6 hours for post-distribution level)
●Serum potassium concentration
●Creatinine and blood urea nitrogen (BUN) to assess renal function
●Serial electrocardiograms (ECGs)
In the setting of an intentional ingestion, the following studies should also be obtained:
●Fingerstick glucose, to rule out hypoglycemia as the cause of any alteration in mental status
●Acetaminophen and salicylate levels, to rule out these common coingestants
●Pregnancy test in women of childbearing age
Electrolyte abnormalities — Inhibition of the sodium-potassium-ATPase, in both heart and skeletal muscle, leads to an increase in extracellular potassium. Thus, hyperkalemia is an important marker of acute cardiac glycoside toxicity, and a predictor of mortality. Other electrolyte abnormalities may also occur in the setting of digoxin poisoning. (See 'Pharmacology and cellular toxicology' above.)
In acute toxicity, the degree of hyperkalemia correlates with mortality. This was first shown in a classic study performed before the advent of antidotal therapy using digoxin-specific antibody (Fab) fragments. In this study of 91 patients primarily with acute digoxin poisoning from intentional overdose, researchers noted that no patient with an initial potassium concentration above 5.5 mEq/L (or mmol/L) survived, while no patient with a potassium concentration below 5 mEq/L died [22]. This correlation has also been demonstrated in plant cardiac glycoside ingestions [23,24].
In the setting of chronic toxicity, hypokalemia is of greater concern. Several electrolyte abnormalities, including hypokalemia, hypomagnesemia, and hypercalcemia, increase patient susceptibility to the toxic effects of digoxin [14]. Loop diuretics to treat heart failure are the most common cause of hypokalemia in these patients, but other causes of hypokalemia (eg, diarrhea or vomiting) do occur.
Renal dysfunction is commonly encountered in the setting of chronic digoxin toxicity and is often what precipitates the rise in the digoxin concentration. Therefore, assessment of renal function is essential and should include measurements of BUN and creatinine, as well as urine output to assess renal perfusion. The adjustments needed for digoxin dosing in the setting of renal insufficiency are described separately. (See "Treatment with digoxin: Initial dosing, monitoring, and dose modification", section on 'Dose adjustments'.)
Serum digoxin concentration: Performance and interpretation — The therapeutic window of digoxin is narrow, with substantial overlap between “therapeutic” and “toxic” serum concentrations (or levels), and the concentration can be affected by many factors (eg, impaired renal function, other medications). Therefore, determining an appropriate therapeutic serum digoxin concentration can be difficult. Issues related to the therapeutic serum concentration of digoxin are reviewed in detail separately. (See "Treatment with digoxin: Initial dosing, monitoring, and dose modification", section on 'Monitoring serum digoxin'.)
A quantitative serum digoxin concentration is readily measured in most hospital laboratories. The approximate therapeutic range for patients in heart failure is 0.5 to 0.8 ng/mL (0.65 to 1 nmol/L), with a typical immunoassay reference range being 0.8 to 2.0 ng/mL (1 to 2.6 nmol/L). Ideally, blood samples should be collected four hours after an intravenous dose or six hours after an oral dose in order to account for drug distribution and obtain an accurate measurement. The serum digoxin concentration is likely to be falsely elevated if the sample is obtained soon after administration or ingestion because of the time required to equilibrate through the large volume of distribution.
The serum digoxin concentration does not necessarily correlate with toxicity. Numerous reports have described asymptomatic patients with a "toxic" level, while others described patients with significant toxicity despite a serum digoxin concentration in the therapeutic range [21,25-27]. Nevertheless, an observational study of 171 digoxin poisonings reported a correlation between a higher mean serum digoxin concentration and 30-day mortality [28].
In the setting of digoxin toxicity, serum digoxin levels can be used to determine the dosing of antidotal therapy with Fab fragments. (See 'Antidotal therapy with antibody (Fab) fragments' below.)
The digoxin immunoassay is specifically designed to measure digoxin; however, cross reactivity with other cardiac glycosides does occur. In cases of toxicity from other cardiac glycosides, such as those found in various plant species, digoxin concentration should not be used to calculate antidotal therapy with Fab fragments due to incomplete cross-reactivity and absence of a correlation between the quantitative result and degree of toxicity.
Following the administration of Fab fragments, serum immunoassays of digoxin are unreliable, as they measure both bound and unbound drug. Fab treatment frequently causes an elevation in the serum digoxin concentration despite a free digoxin level approaching zero [29,30]. Consequently, total digoxin levels should not be obtained or used clinically following Fab fragment administration. Measurement of "free" digoxin concentrations may be utilized and followed after treatment with Fab fragments, although free digoxin level may not be routinely available in some centers.
Elevated digoxin levels have been identified in pregnant women, newborns, and patients with acromegaly, subarachnoid hemorrhage, liver disease, and renal failure due to endogenous digoxin-like substances [31]. The clinical significance of endogenous digoxin-like substances remains unknown.
Electrocardiogram — Cardiac glycoside toxicity can produce a range of cardiac dysrhythmias, and rhythm disturbances may evolve and change rapidly. Thus, performing continuous cardiac monitoring and obtaining serial electrocardiograms (ECG) is important in the setting of toxicity. An ECG should be obtained upon presentation and repeated with any change in the patient's clinical condition or any significant alteration in the rhythm or waveform on the cardiac monitor.
Premature ventricular contractions are the most common rhythm disturbance caused by digoxin toxicity [32]. Others include bradycardia, atrial tachydysrhythmias with AV block, ventricular bigeminy, junctional rhythms, various degrees of AV nodal blockade, ventricular tachycardia, and ventricular fibrillation. Bidirectional ventricular tachycardia, while not pathognomonic for digoxin toxicity, is encountered in rare instances; digoxin is one of only a few xenobiotics known to produce this dysrhythmia (waveform 1).
Ventricular dysrhythmias are reportedly more common in chronic toxicity and in patients with chronic heart disease [25]. A detailed description of the dysrhythmias caused by cardiac glycosides is found separately. (See "Cardiac arrhythmias due to digoxin toxicity".)
The so-called "digitalis effect" on the ECG consists of T wave changes (flattening or inversion), QT interval shortening, scooped ST segments with ST depression in the lateral leads, and increased amplitude of the U waves. It is often seen with chronic digoxin use and does not correlate well with clinical manifestations of toxicity (waveform 2) [10].
DIAGNOSIS — The diagnosis of cardiac glycoside toxicity is made clinically based upon a combination of a history of exposure, suggestive clinical features, and/or electrocardiographic manifestations. Isolated elevated serum digoxin concentrations may confirm exposure but do not correlate consistently with clinical manifestations of toxicity. Following an acute overdose, the patient may remain asymptomatic for several hours and then manifest a number of symptoms and signs, including cardiac (dysrhythmia), gastrointestinal (anorexia, nausea, vomiting, and abdominal pain), and neurologic findings (confusion, weakness, delirium). The cardiac manifestations of cardiac glycoside toxicity can include virtually any type of dysrhythmia, with the exception of rapidly conducted atrial dysrhythmias. Hyperkalemia is an important marker of and prognostic indicator for acute toxicity. Chronic toxicity is often more difficult to diagnose, as symptom onset tends to be more insidious and digoxin concentrations may be minimally elevated.
DIFFERENTIAL DIAGNOSIS — Poisoning with beta blockers, calcium channel blockers, and alpha agonists (eg, clonidine) can present in a similar fashion to digoxin toxicity, with bradycardia and hypotension being prominent features. An elevated serum digoxin concentration distinguishes digoxin poisoning. In addition, significant toxicity from calcium channel blockers generally produces hyperglycemia. Clonidine poisoning leads to greater CNS depression, respiratory depression, and miosis than is seen with digoxin poisoning.
Nontoxicologic etiologies may also present with symptoms and signs similar to cardiac glycoside poisoning. These may include sick-sinus syndrome, hypothermia, hypothyroidism, myocardial infarction, and hyperkalemia from other causes.
MANAGEMENT
Basic measures and dysrhythmias — When cardiac glycoside toxicity is suspected, the following measures should be performed:
●Assess airway, breathing, and circulation; stabilize as necessary
●Place the patient on continuous cardiac and pulse oximetry monitors
●Establish intravenous (IV) access
●Obtain an electrocardiogram (ECG)
●Obtain a fingerstick glucose measurement if there is any alteration in mental status (see 'Approach to testing' above)
The treatment for any clinically significant dysrhythmia from cardiac glycoside toxicity, particularly those producing hemodynamic instability, is digoxin-specific antibody (Fab) fragments. Treatment decisions must be made on an individual basis and are often made in conjunction with a medical toxicologist or a poison control center. (See 'Additional resources' below.)
As temporizing measures or if Fab fragments are not immediately available, symptomatic bradycardia or bradydysrhythmia can be treated with atropine (0.5 mg IV in adults; 0.02 mg/kg IV in children, minimum dose 0.1 mg) and hypotension with IV boluses of isotonic crystalloid. In patients with history of decompensated heart failure, judicious use of fluids may be required. Life-threatening ventricular dysrhythmias are treated according to the algorithms of advanced cardiac life support. (See "Advanced cardiac life support (ACLS) in adults".)
Antidotal therapy with antibody (Fab) fragments
Indications and general approach — Early recognition of cardiac glycoside toxicity and prompt administration of Fab fragments is essential for the successful treatment of severe poisoning [12,33]. Fab fragments are highly effective and safe and have transformed the management of cardiac glycoside poisoning [33,34]. One vial binds approximately 0.5 mg of digoxin.
The dosing of Fab fragments is based upon the clinical setting (eg, agent and amount ingested; serum digoxin concentration) and is discussed in detail separately. (See "Dosing regimen for digoxin-specific antibody (Fab) fragments in patients with digoxin toxicity".)
Fab fragments should be given in all cases of severe cardiac glycoside poisoning, as there is no alternative therapy with comparable efficacy and safety. We suggest Fab fragments be given to patients with digoxin toxicity and any of the following:
●Life-threatening or hemodynamically unstable dysrhythmia (eg, ventricular tachycardia; ventricular fibrillation; asystole; complete heart block; Mobitz II heart block; symptomatic bradycardia) [35]
●Hyperkalemia (serum potassium >5 to 5.5 meq/L [>5 to 5.5 mmol/L])
●Evidence of end-organ dysfunction from hypoperfusion (eg, renal failure, altered mental status)
We generally do not advocate treatment with Fab fragments based solely upon the serum digoxin concentration or the amount ingested; treatment is predicated on the clinical manifestations described above. However, some advocate giving Fab fragments if the serum digoxin concentration is greater than 10 ng/mL (13 nmol/L) at steady state in acute ingestions, or greater than 4 ng/mL (5.1 nmol/L) in chronic ingestions, or when an adult ingests more than 10 mg or a child more than 4 mg acutely.
Cross reactivity exists between digoxin and other cardiac glycosides. Therefore, digoxin-specific antibodies can be used to treat poisoning involving cardiac glycosides from both plants and animals [23,36,37]. However, the dosing of Fab fragments should be done empirically in such cases because the degree of toxicity in naturally occurring cardiac glycosides does not correlate with the serum digoxin concentration. (See 'Serum digoxin concentration: Performance and interpretation' above.)
The advent of digoxin-specific antibody (Fab) fragments occurred in 1976 [25,38]. Evidence for the benefit of Fab fragments is found in the many case series that have appeared since that time [34,39]. Prior to the development of this treatment, the management of digoxin overdose was difficult and often resulted in life-threatening dysrhythmias.
Patients with pacemakers — It may be impossible to determine the underlying cardiac rhythm and thereby detect signs of cardiac glycoside toxicity in patients with paced rhythms. The ECG in such patients may demonstrate a paced rhythm without ventricular ectopy or bradydysrhythmia despite the presence of moderate to severe digoxin toxicity. We suggest treating these patients with digoxin-specific antibody fragments if the serum potassium concentration is above 5 to 5.5 meq/L [>5 to 5.5 mmol/L] or clinical symptoms are significant (eg, encephalopathy) or progressing. (See 'Clinical manifestations' above.)
GI decontamination — The administration of activated charcoal (AC) or cholestyramine for gastrointestinal decontamination should be viewed as adjunctive and not primary therapy in patients with digoxin poisoning.
Patients suspected of having an acute cardiac glycoside intoxication who present to the emergency department within one to two hours of ingestion may benefit from the administration of AC. The standard dose is 1 g/kg (maximum 50 g). The decision to administer AC should be made after ensuring that the patient is alert and adequately protecting their airway. We do not advocate insertion of a nasogastric tube in a nonintubated patient solely for the purpose of administering AC. AC is unlikely to benefit patients with chronic digoxin toxicity.
Cardiac glycosides undergo some degree of enterohepatic or enteroenteric recirculation and are adsorbed to activated charcoal. However, there are mixed clinical data regarding the efficacy of AC or multi-dose AC (MDAC) in the setting of yellow oleander poisoning: One randomized trial found a reduction in mortality with AC administration [40], while another did not [41].
When Fab fragments are not available, AC or MDAC are reasonable interventions in patients with yellow oleander poisoning, although efficacy remains unclear. The extrapolation of data from studies of yellow oleander poisoning to poisonings with other glycosides (eg, digoxin) should be made with caution. Most importantly, neither AC nor MDAC should ever be considered an alternative to Fab fragment therapy for any cardiac glycoside poisoning when Fab fragments are available. Fab fragment therapy remains the essential treatment for cardiac glycoside poisoning. (See 'Antidotal therapy with antibody (Fab) fragments' above.)
Cholestyramine may interrupt enterohepatic recirculation and its use has been reported in patients with acute digoxin intoxication and renal failure for whom Fab fragments were not available [42,43]. Its use cannot be recommended generally given the limited data; if used, the dose is 4 g by mouth, given twice daily.
Electrolyte abnormalities
Hyper- and hypo-kalemia — Hyperkalemia accurately reflects the degree of toxicity and risk of death in acute digoxin intoxication. Hyperkalemia itself does not cause death, and treatment with potassium-lowering agents such as insulin and dextrose, sodium bicarbonate, or ion exchange resins does not reduce mortality [22].
Once treatment with digoxin-specific antibody (Fab) fragments is instituted, hyperkalemia due to cardiac glycoside toxicity is rapidly corrected as the sodium-potassium ATPase function returns and pumps potassium back into cells. Thus, aggressive treatment with potassium-lowering agents could cause significant hypokalemia following antidotal therapy. If the hyperkalemia is thought to be due to underlying renal failure, however, treatment of hyperkalemia with use of potassium-binding resins, sodium bicarbonate, or insulin/glucose may be utilized.
If a patient with digoxin poisoning is hypokalemic, potassium should be administered since hypokalemia exacerbates digitalis toxicity [21]. The need for potassium repletion is particularly important for patients treated with Fab fragments, because this treatment leads to a further reduction in the serum potassium. Many patients with hypokalemia may have coexistent hypomagnesemia, which should be corrected as well. (See "Clinical manifestations and treatment of hypokalemia in adults".)
Should calcium be administered for hyperkalemia? — Because hyperkalemia is not the cause of death and because excessive intracellular calcium is present in digoxin poisoning, we do not recommend routine administration of calcium in hyperkalemic patients with recognized digoxin toxicity. In this setting, hyperkalemia is best treated with digoxin-specific antibody fragments. (See 'Antidotal therapy with antibody (Fab) fragments' above.)
Some suggest that calcium should not be given to patients with digoxin toxicity for the treatment of hyperkalemia, but high-quality evidence is lacking. This teaching is based primarily upon five published cases dating back to 1933. Of these five cases, only three patients had a temporal association between calcium administration and digoxin toxicity [44-46]. Some studies have shown that hypercalcemic animals given digoxin developed adverse effects with lower doses than normocalcemic animals [47,48]. However, the serum calcium concentrations in these studies exceeded 20 mg/dL (5 mmol/L) before increased toxicity occurred. Other animal experiments involving lower, more physiologic, serum calcium concentrations did not show increased toxicity [49].
There are several case reports of patients receiving calcium for treatment of digoxin-induced hyperkalemia without adverse effects [50,51]. In addition, a large retrospective series of patients with digoxin toxicity found no ill effects attributable to the administration of calcium [52].
Renal failure
General care — Volume depletion from diuretics or gastrointestinal losses can cause prerenal disease, contributing to digoxin toxicity. Appropriate fluid resuscitation is necessary in such cases. (See "Etiology, clinical manifestations, and diagnosis of volume depletion in adults".)
Fab fragment dosing — The dose of digoxin-specific antibody (Fab) fragments does not need to be adjusted in patients with renal failure, but the elimination of both digoxin and Fab fragments is markedly prolonged in this setting [53-55]. Cases of recurrent digoxin toxicity, including ventricular dysrhythmias, have been reported 72 to 90 hours after antidotal therapy [29]. Thus, any patient with significant renal dysfunction who receives Fab fragments should be observed in a closely monitored setting for a minimum of 72 hours.
Extracorporeal removal — Because of digoxin's large volume of distribution and molecular weight, extracorporeal removal is not beneficial. Neither hemoperfusion nor hemodialysis has been shown to be helpful in the management of digoxin toxicity [56-58].
The combination of Fab fragments and plasmapheresis has been used with apparent success in a few patients with renal failure [59,60]. Nevertheless, we do not routinely recommend this approach. Instead, we administer Fab fragments for the usual indications and observe the patient with renal failure in a closely monitored setting over several days. Additional Fab fragments are given if signs of toxicity recur.
Disposition — All patients with signs of cardiac glycoside toxicity should be admitted to the hospital with continuous cardiac monitoring. Patients who have unstable cardiac rhythms and those with underlying cardiac disease or major comorbidities are admitted to an intensive care setting.
Patients with less severe signs of cardiac glycoside toxicity who do not receive antidotal therapy with Fab fragments are admitted for monitoring, which should include serial measurements of their serum potassium and digoxin concentrations. Serial electrocardiograms (ECG) should be obtained. Although the time interval for obtaining ECGs will vary depending on the patient's clinical condition, a new ECG should be obtained if any significant changes are noted on the cardiac monitor.
Patients with suspected cardiac glycoside toxicity but without significant manifestations or renal disease are placed on cardiac monitoring and observed for approximately six hours. If they remain asymptomatic and a repeat serum digoxin concentration is not increasing, they may be discharged.
PEDIATRIC CONSIDERATIONS — While less common, pediatric ingestions of digoxin are potentially life threatening [61]. Toxicity among children generally presents with signs and symptoms similar to adults, but with a few important exceptions. Children are more likely to present with bradydysrhythmias and heart block, rather than ventricular dysrhythmias [62]. In addition, children may be more resistant to digoxin's cardiotoxic effects than adults at an equivalent serum concentration [25].
The treatment of digoxin toxicity, including the indications for antidotal therapy with digoxin-specific antibody (Fab) fragments, remains unchanged. The dosing of Fab fragments is based upon the clinical setting (eg, agent and amount ingested; serum digoxin concentration) and is discussed in detail separately. The indications for treatment are described above. (See "Dosing regimen for digoxin-specific antibody (Fab) fragments in patients with digoxin toxicity" and 'Antidotal therapy with antibody (Fab) fragments' above.)
In addition to ingesting digoxin, children may ingest cardiac glycoside-containing plants with resultant toxic effects. The diagnosis and management of such ingestions is reviewed separately. (See "Potentially toxic plant ingestions in children: Clinical manifestations and evaluation", section on 'Cardiac glycosides (eg, oleander, foxglove)' and "Toxic plant ingestions in children: Management".)
ADDITIONAL RESOURCES
Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)
Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment".)
SUMMARY AND RECOMMENDATIONS
●Clinical manifestations – The clinical manifestations of digoxin (cardiac glycoside) toxicity include cardiac, gastrointestinal, and neurologic signs. Chronic toxicity is more difficult to diagnose, as symptom onset tends to be more insidious. (See 'Clinical features and diagnosis' above.)
•Dysrhythmia is the most dangerous manifestation of cardiac glycoside poisoning and can include virtually any type of dysrhythmia with the exception of rapidly conducted atrial dysrhythmias.
•Gastrointestinal effects include anorexia, nausea, vomiting, and abdominal pain.
•Neurologic signs such as confusion and weakness may be present. Visual changes may occur, including alterations in color vision, the development of scotomas, or blindness.
●Differential diagnosis – The differential diagnosis for cardiac glycoside intoxication includes poisoning with beta blockers, calcium channel blockers, or alpha agonists (eg, clonidine), as well as nontoxicologic etiologies such as sick-sinus syndrome, hypothermia, hypothyroidism, myocardial infarction, and hyperkalemia unrelated to digoxin. (See 'Differential diagnosis' above.)
●Laboratory and electrocardiogram (ECG) evaluation – In the patient with suspected digoxin toxicity, a serum digoxin concentration, serum potassium concentration, creatinine and blood urea nitrogen (BUN), and serial ECGs should be obtained. (See 'Laboratory and ECG evaluation' above.)
●Diagnosis – The diagnosis of cardiac glycoside toxicity is made clinically based upon a combination of a history of exposure, suggestive clinical features, and/or ECG manifestations. Isolated elevated serum digoxin concentrations may confirm exposure but do not correlate consistently with clinical manifestations of toxicity. The therapeutic range of serum digoxin is 0.8 to 2 ng/mL (1 to 2.6 nmol/L). (See 'Diagnosis' above and 'Serum digoxin concentration: Performance and interpretation' above.)
●Overview of management – Management includes standard supportive care; assessing and stabilizing airway, breathing, and circulation; gastrointestinal decontamination; and antidotal therapy with digoxin-specific antibody (Fab) fragments. (See 'Management' above.)
•As temporizing measures, bradycardia can be treated with atropine (0.5 mg intravenously [IV] in adults, 0.02 mg/kg IV in children, minimum dose 0.1 mg).
•Hypotension is likely due to underlying dysrhythmia, which should be addressed. If hypovolemia is suspected, administer IV boluses of isotonic crystalloid. (See 'Basic measures and dysrhythmias' above.)
•In patients with history of decompensated heart failure or kidney failure, judicious use of fluids may be required.
•Hyperkalemia reflects the degree of toxicity and risk of death in acute cardiac glycoside intoxication. Aggressive treatment of hyperkalemia does not reduce mortality and may increase the risk of hypokalemia following treatment with Fab fragments. Thus, aggressive management of hyperkalemia is typically not warranted. (See 'Electrolyte abnormalities' above.)
●Gastrointestinal decontamination – Patients suspected of having acute cardiac glycoside intoxication who present to the emergency department within one to two hours of ingestion may benefit from the administration of activated charcoal. The standard dose is 1 g/kg (maximum 50 g). The decision to administer activated charcoal should be made after ensuring that the patient is alert and adequately protecting their airway. (See 'GI decontamination' above.)
●Digoxin-specific Fab fragments – In a patient with clinically significant manifestations of cardiac glycoside poisoning, we recommend treatment with digoxin-specific Fab fragments (Grade 1B). Significant findings include (see 'Antidotal therapy with antibody (Fab) fragments' above):
•Life-threatening dysrhythmia (eg, ventricular tachycardia; ventricular fibrillation; asystole; complete heart block; Mobitz II heart block; symptomatic bradycardia)
•Evidence of end-organ dysfunction (eg, renal failure, altered mental status)
•Hyperkalemia (serum potassium >5 to 5.5 meq/L [>5 to 5.5 mmol/L])
●Digoxin concentration monitoring after digoxin-specific Fab administration – In a patient who received antidotal therapy with Fab fragments, total digoxin concentrations should not be obtained as they measure both bound (inactive) and unbound drug. Monitoring of clinical response is typically sufficient, but if concentration monitoring is needed, only free serum digoxin concentrations can be interpreted. (See 'Serum digoxin concentration: Performance and interpretation' above.)
