CARDIAC GLYCOSIDES

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Cardioactive Steroids (synonym)
2) Carditoxin (synonym)
3) Deslanoside (synonym)
4) Digitalis Glycoside (synonym)
5) Digitalis leaf (synonym)
6) Digitoxin (synonym)
7) Digoxin (synonym)
8) Lanatoside C (synonym)
9) Lanoxin (synonym)
10) Ouabain (synonym)
11) CAS 20830-75-5 (Digoxin) (synonym)
12) CAS 71-63-6 (Digitoxin) (synonym)
13) CAS 36-06-6 (Ouabain) (synonym)
14) CAS 630-60-4 (Ouabain) (synonym)

Available Forms Sources

1) DIGOXIN: 0.05 mg, 0.1 mg, and 0.2 mg capsules; 0.125 mg and 0.25 mg tablets; 0.05 mg/mL pediatric elixir; 0.25 mg/mL injection; 0.1 mg/mL pediatric injection (USP-DI, 2001).
2) DIGITOXIN: 0.1 mg tablets (available in Canada) (USP-DI, 2001).
3) DESLANOSIDE: 0.2 mg/mL injection (no longer available in the United States)

1) Cardiac glycosides are contained in digitalis leaf, foxglove (Digitalis purpurea), Lilly of the Valley (Convallaria majalis), oleander (Nerium oleander), Digitalis lanata, Strophantus kombe/gratis, hispidus seeds, squill (Urginea maritima/indica bulbs), Dogbane (Apocynum cannabinum), Adonis vernalis, and Thevetia peruviana.
2) Acetyldigitoxin is a crystalline glycoside derived from Digitalis lanata and is the natural occurring cardiac glycoside defined as the alpha acetyl ester of digitoxin.

1) These drugs are indicated for the treatment of mild to moderate heart failure and for control of ventricular response rate in patients with chronic atrial fibrillation. Digoxin increases left ventricular ejection fraction resulting in improvement of heart failure symptoms. Digoxin is often used in conjunction with a diuretic and an angiotensin-converting enzyme inhibitor for the treatment of heart failure (Prod Info LANOXICAPS(R) oral capsules, 2005).

Overview

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Patients who do not develop significant cardiac toxicity require only supportive care and monitoring. Patients with mild bradycardia and nonspecific symptoms from chronic poisoning should be monitored and rehydrated, but do not require specific therapy.

B) MANAGEMENT OF SEVERE TOXICITY

1) Following acute ingestion, patients with hyperkalemia (greater than 5 mEq/L), symptomatic bradycardia, ventricular ectopy, or dysrhythmias should be treated with digoxin immune Fab. Digoxin immune Fab is also indicated for patients with chronic toxicity with ventricular ectopy or symptomatic bradycardia. If digoxin immune Fab is not available, patients can be treated with atropine or cardiac pacing for bradycardia and antidysrhythmics (lidocaine or amiodarone) for ventricular ectopy or dysrhythmias. Other treatments have been suggested. Phenytoin (100 mg to 300 mg IV bolus) and magnesium sulfate (2 g) have both been anecdotally reported to produce resolution of dysrhythmias from cardiac glycoside poisoning. Finally, cardiac pacing (at a rate that exceeds cardiac ectopy) can be used for patients who do not respond to medical management.

C) DECONTAMINATION

1) PREHOSPITAL: Emesis is not recommended for cardiac glycoside ingestion. Activated charcoal should be given to patients who can protect their airway and are not actively vomiting.
2) HOSPITAL: Cardiac glycosides are well adsorbed by charcoal; administration of charcoal should be considered in all cases that present within 1 to 2 hours of ingestion.

D) AIRWAY MANAGEMENT

1) Airway protection is mandatory in patients with altered mental status.

E) ANTIDOTE

1) The antidote for cardiac glycoside poisoning is digoxin immune Fab (digoxin immune antibody fragment) which rapidly reverses the effect of cardiac glycosides.
2) INDICATIONS: Indications for digoxin immune Fab include manifestations of severe toxicity (ventricular dysrhythmias, progressive bradyarrhythmias, 2nd or 3rd degree heart block), refractory hypotension, hyperkalemia (greater than 5 mEq/L in acute overdose), significant risk of cardiac arrest (ingestion greater than 10 mg in an adult or greater than 4 mg in a child, serum digoxin concentration greater 10 ng/mL post-distribution [generally 6 hours after ingestion]), or lack of response to conventional therapy. The appropriate dose can be calculated from either the ingested dose or the steady state serum digoxin concentration.
3) BY INGESTED DOSE: The digoxin immune Fab dose (in vials) equals the ingested dose of capsules (in mg) divided by 0.5 mg per vial OR the ingested dose of tablets (in mg) multiplied by 0.8 (for 80% bioavailability) and divided by 0.5 mg per vial.
4) BY STEADY STATE CONCENTRATION: The digoxin immune Fab dose (in vials) equals the steady state serum digoxin concentration (in ng/mL) multiplied by the patient weight (in kg) divided by 100. Administer 10 to 20 vials for critically ill patients or patients in cardiac arrest.
5) ADVERSE EFFECTS: Allergic reactions are rare, but can happen, especially in patients with a history of asthma and/or allergy to antibiotics. Hypokalemia, worsening of heart failure, and loss of ventricular rate control can also occur.

F) ENHANCED ELIMINATION

1) Hemodialysis does not increase the clearance of digoxin. Multiple dose charcoal enhances digoxin clearance and may be considered in a patient who can protect their airway if digoxin immune Fab is not available.

G) PATIENT DISPOSITION

1) OBSERVATION CRITERIA: Patients who have only GI symptoms and a clearly decreasing serum digoxin concentration can be discharged after a minimum of 8 hours of observation.
2) ADMISSION CRITERIA: Admit all patients, who develop dysrhythmias, heart block, severe vomiting, or who require digoxin immune Fab treatment, to an ICU setting. Admit patients to a monitored setting if they have digoxin concentrations that are not clearly declining during 8 hours of observation.

H) PITFALLS

1) Digoxin has a slow redistribution phase, so high serum concentrations are expected for several hours following doses. A single high digoxin concentration in an otherwise asymptomatic patient is not an indication for treatment. Severe toxicity from cardiac glycosides is very difficult to treat if digoxin immune Fab is not available. Serum digoxin concentrations will rise after digoxin immune Fab treatment if the assay used does not distinguish free from bound digoxin.

I) PHARMACOKINETICS

1) Digoxin is concentrated in tissues and therefore has a large volume of distribution. Time to onset of action is about 0.5 to 2 hours after oral dosing and peaks at 2 to 6 hours, and is excreted unchanged by the kidney. The elimination half-life is about 30 to 45 hours for a therapeutic level in a patient with normal renal function. Digitoxin is extensively metabolized by the liver, primarily excreted in bile, and has an elimination half-life of about 4 to 7 days.

J) TOXICOKINETICS

1) Digoxin half-life may be prolonged in overdose (72 to 94 hours).

K) DIFFERENTIAL DIAGNOSIS

1) The differential diagnosis should include other causes of bradycardia, heart block, altered mental status, and hypotension, including calcium channel antagonists, beta-blockers, clonidine, and medical causes such as acute myocardial infarction or hypoxia.

Range Of Toxicity

Life Support

Clinical Effects

0.2.1)

A) USES: Cardiac glycosides are medications derived from naturally occurring toxins; digitalis is the most widely used, digitoxin is used outside the US. Plants and animals that contain cardiac glycosides are covered in separate managements. Cardiac glycosides are used for congestive heart failure and for ventricular rate control in atrial fibrillation.
B) PHARMACOLOGY: Cardiac glycosides inhibit the sodium-potassium ATPase pump. The increase in intracellular sodium leads to increased activity of the sodium-calcium exchanger, which elevates intracellular calcium and improves cardiac contractility. Cardiac glycosides also increase cardiac vagal tone which decreases cardiac sympathetic activity.
C) TOXICOLOGY: The effects in overdose are an extension of the therapeutic effects. Increased intracellular calcium leads to early afterdepolarization, cardiac irritability, and dysrhythmias. Increased vagal and decreased sympathetic tones lead to bradycardia and heart block. Inhibition of the sodium-potassium ATPase pump causes hyperkalemia.
D) EPIDEMIOLOGY: Cardiac glycoside toxicity is uncommon, but severe toxicity and deaths may occur. Most cases are due to exposure to pharmaceuticals, but occasionally patients will develop symptoms after ingestion of plant or animal products containing cardiac glycosides.
E) WITH THERAPEUTIC USE

1) Headache, fatigue, stupor, gynecomastia, skin rash, and thrombocytopenia have been associated with chronic use.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Toxicity from cardiac glycosides can be acute (from a single overdose due to accidental ingestion by a child or due to a self-harm attempt by an adult) or chronic toxicity (due to increased dosing or decreased drug clearance). The manifestations and treatment are slightly different. The most common symptoms following acute ingestion are nausea, vomiting, abdominal pain, lethargy, and bradycardia. With chronic toxicity, patients often present with bradycardia, malaise, nausea, anorexia, delirium, and vision changes.
2) SEVERE TOXICITY: Patients with acute poisoning may develop severe bradycardia, heart block, vomiting, and shock. Hyperkalemia is a marker of severe acute toxicity and serum potassium is the best predictor of cardiac glycoside toxicity after acute overdose. Severe chronic toxicity causes ventricular dysrhythmias and varying degrees of heart block, but hyperkalemia is uncommon.

0.2.20)

A) Digoxin has been classified as FDA pregnancy category C. There are no adequate and well-controlled studies of digoxin in pregnant women. Animal studies have not been conducted. Congenital anomalies and perinatal problems have not been linked with cardiac glycoside use during pregnancy. Digoxin can be used in pregnancy, but may require dosage adjustments due to increased plasma volume, decreased protein binding, and increased renal excretion in the pregnant patient. Digoxin has been used in pregnant women without apparent harm to the mother or fetus. The fetus is able to metabolize digoxin and excretes it in the bile. Low birth weight has been observed in infants of mothers receiving digitalis glycosides, presumably due to decreased gestational age and not due to intrauterine growth retardation. In addition, adverse effects to the fetus have been found when the mother develops digitalis toxicity. As it is unknown whether digoxin causes fetal harm when administered during pregnancy, it is recommended that the drug be administered in pregnant women only if clearly necessary.

0.2.21)

A) Digoxin has been associated with chronic lymphocytic leukemia, but data are lacking to assess the potential carcinogenic activity of digoxin.

Laboratory Monitoring

Clinical Effects

Summary Of Exposure

1) Headache, fatigue, stupor, gynecomastia, skin rash, and thrombocytopenia have been associated with chronic use.

Heent

3.4.2)

A) WITH THERAPEUTIC USE

1) CASE REPORT: A 62-year-old man on chronic digoxin therapy (0.25 mg/day) developed taste disturbances. An electric gustometer and measurement with a filter paper disk indicated a diminished sense of sweet, bitter, and salt tastes. At the same time, the patient also experienced decreased visual acuity and a decreased sense of smell. Laboratory studies showed that his serum digoxin level peaked at 6 ng/mL (normal 1.9 ng/mL). Digoxin therapy was discontinued and all of the patient's sensory disturbances resolved following normalization of his serum digoxin level (Ishimaru & Yokogawa, 2006).

3.4.3)

A) VISUAL DISTURBANCES: Photophobia, amblyopia, aberrations of color vision (predominance of yellow-green), decreased visual acuity, miosis, and scotoma may occur, but generally are seen only in chronic digitalis toxicity.

1) Cones are 50-fold more sensitive than rods. Inhibition of light response by photoreceptors is concentration-dependent and reversible (Madreperla et al, 1994).

a) CASE REPORT: Piltz et al (1993) report the case of an 88-year-old woman presenting to the emergency department with decreased visual acuity and an increased serum digoxin level (Piltz et al, 1993). Electroretinographic (ERG) studies suggested a cone deficit implicating a retinal dysfunction.
b) CASE REPORT: A 62-year-old man on chronic digoxin therapy (0.25 mg/day) developed photophobia with decreased visual acuity, as well as taste and olfactory disturbances. Laboratory studies showed that his serum digoxin level peaked at 6 ng/mL (normal 1.9 ng/mL). Digoxin therapy was discontinued and all of the patient's sensory disturbances resolved following normalization of his serum digoxin level (Ishimaru & Yokogawa, 2006).
c) CASE REPORT: Diplopia and blurred and yellow vision were reported in a 30-year-old woman following intentional ingestion of 70 0.25-mg digoxin tablets (total dose 17.5 mg). Serum digoxin level was 12.63 ng/mL (normal range 0.8 to 2 ng/mL) (Juneja et al, 2012).

B) CORNEAL EDEMA: Topical application of digitoxin (0.02 mg/10 mL) and digoxin (25 mg/100 mL resulted in corneal edema. The effects appeared to be reversible upon discontinuation of the medication (Grant & Schuman, 1993).
C) CONE DYSFUNCTION: Electroretinography revealed cone dysfunction in dogs poisoned with digitalis (Maehara et al, 2005).
D) PHOTOPSIA: A 72-year-old woman, who was taking 0.125 mg of digoxin daily, developed a sudden onset of binocular photopsia. A review of her history revealed that she had diarrhea and appetite loss for 10 days. Laboratory analysis showed a serum creatinine level of 1.8 mg/dL, a serum potassium level of 5.7 mEq/L, and a serum digoxin level of 1.70 ng/mL . The photopsia resolved following discontinuation of digoxin therapy and administration of fluids (Oishi et al, 2006).

3.4.5)

A) WITH THERAPEUTIC USE

1) CASE REPORT: A 62-year-old man on chronic digoxin therapy (0.25 mg/day) developed a decreased sense of smell, along with decreased visual acuity and taste disturbances. Laboratory studies showed that his serum digoxin level peaked at 6 ng/mL (normal 1.9 ng/mL). Digoxin therapy was discontinued and all of the patient's sensory abnormalities resolved following normalization of his serum digoxin level (Ishimaru & Yokogawa, 2006).

Cardiovascular

3.5.2)

A) CONDUCTION DISORDER OF THE HEART

1) WITH THERAPEUTIC USE

a) Exercise-induced ventricular tachycardia and a widened QRS complex were reported in a patient 2 weeks after therapy with digoxin (0.25 mg/day) had been instituted. The dysrhythmia produced no symptoms and terminated spontaneously after 25 seconds (Gosselink et al, 1993).
b) CASE REPORT: A 6-month-old infant, experiencing persistent tachycardia (140 to 230 bpm) and an increase in serum creatinine levels (from 67 mcmol/L to 99 mcmol/L) after cardiac surgery, received 3 doses of intravenous digoxin (0.16 mg, 0.08 mg, and 0.08 mg). Despite digoxin administration, there was no improvement in the patient's tachycardia and the serum creatinine level increased to 134 mcmol/L with complete anuria. Serum digoxin concentration, obtained 24 hours after initiation of digoxin therapy, was 8.1 nmol/L. The patient's serum potassium level was elevated, peaking at 7.8 mmol/L, and she developed an AV junctional tachycardia (300 bpm). Digibind(R) was initiated intravenously at a bolus dose of 14.2 mg and, 1 minute later, the AV junctional tachycardia converted to regular sinus rhythm at a rate of 140 bpm and, 20 minutes later, the patient's potassium level normalized to 4.5 mmol/L (Husby et al, 2003). The authors speculated that the toxic digoxin levels may have been due to a too rapid administration of the 0.08 mg follow-up doses in a patient with renal impairment.
c) CASE REPORT: An 86-year-old woman, taking 0.25 mg of digoxin daily for chronic atrial fibrillation, developed cardiac arrest. She was successfully resuscitated following electrical cardioversion. An ECG revealed alternating QRS complexes with a regularity of tachycardia characteristic of bidirectional ventricular tachycardia. Laboratory studies showed a serum creatinine level of 10 mg/L, a creatinine clearance of 45 mL/min, and a serum digoxin level of 13 ng/mL (normal is less than 2). A review of her medication history revealed that in addition to digoxin, the patient was also taking perindopril, fosinopril, isosorbide dinitrate, and acetylsalicylic acid. It is believed that a combination of dehydration and several nephrotoxic medications, leading to decreased renal function, may have resulted in digoxin toxicity. The patient recovered with supportive care (Grimard et al, 2005).
d) CASE REPORT: A 79-year-old woman, with a history of congestive heart failure and persistent atrial fibrillation, developed bidirectional tachycardia followed by ventricular fibrillation approximately 20 days after initiating therapy with IV digoxin 0.125 mg daily and approximately 14 days after receiving hemodialysis for acute renal failure. Her serum digoxin and potassium concentrations were 2.4 ng/mL and 2.7 mEq/L, respectively. The patient recovered following successful defibrillation (Kaneko et al, 2011).

2) WITH POISONING/EXPOSURE

a) SUMMARY: The hallmark of digitalis poisoning is increased automaticity coupled with concomitant conduction delay. Every known type of dysrhythmia has been associated with digitalis intoxication, including bradycardia, all degrees of heart block, PAT with block, bundle branch block, nodal tachycardia with A-V dissociation, atrial and ventricular ectopy, and ventricular tachycardia and fibrillation; any or all may occur in the same patient (Rodensky & Wasserman, 1961; Bhatia & Smith, 1987; Soffer, 1961; Lyon & DeGraff, 1967; Gould et al, 1986; Nordt et al, 1998; Caspi et al, 1997; Fenton et al, 1996; Ma et al, 2001; Guijarro-Morales et al, 2002).

1) Although no single dysrhythmia is always present, commonly appearing aberrations include frequent premature ventricular contractions, bradydysrhythmias, paroxysmal atrial tachycardia with high degree atrioventricular block, and junctional tachycardia. Bidirectional ventricular tachycardia is rare but pathognomonic (Ma et al, 2001).
2) In a case of an intentional overdose (probably 5 to 10 mg), an unusual ECG pattern was seen in a 46-year-old woman with no cardiac symptoms. Initial ECG revealed slow ventricular repolarization (33 beats/minute) characterized by apparent QT-interval prolongation and a QT-interval dispersion. Prominent and prolonged U-waves were also seen (Lanzarini et al, 2002).
3) PEDIATRIC EXPOSURE: The most common presenting symptoms in a pediatric patient are gastrointestinal complaints, sinus bradycardia, or first-degree AV block (Morini et al, 2003; Gittelman et al, 1999).

b) Torsades de Pointes may also occur with digitalis toxicity (Bhatia & Smith, 1987).
c) Atrial and ventricular ectopy appear to be more common in patients with underlying heart disease (Hickey et al, 1991).

1) CASE REPORT: Digitoxin toxicity was reported in a 79-year-old man who had been taking digitoxin for 2 years and who also was taking therapy for atrial fibrillation. The patient experienced ventricular ectopy which correlated well with his serum digitoxin concentration and was apparently precipitated by adrenergic drive during exertion (Lehmann et al, 2000).

d) In 1 study involving 29 pediatric patients with severe digitalis poisoning, atrioventricular block was the most common sign of toxicity, occurring in 76% of the patients (Woolf et al, 1992).
e) Chan et al (1995) describe an unusual bidirectional ventricular tachycardia associated with digoxin toxicity in a 55-year-old man with new onset renal insufficiency. Resolution of the tachycardia occurred following Digibind (Chan et al, 1995).
f) CASE REPORT: A 22-month-old boy presented to the emergency department the day following ingestion of an unknown quantity of digoxin tablets. ECG revealed a Mobitz 1, second-degree heart block with a PR interval of 0.20 seconds. A digoxin level of 11.9 ng/mL was reported (Gittelman et al, 1999).
g) CASE REPORT: A 30-year-old woman developed persistent vomiting, diplopia, blurred and yellow vision, and intermittent episodes of bradycardia with hypotension after ingesting 70 0.25-mg digoxin tablets (total dose 17.5 mg). An initial serum digoxin level was 12.63 ng/mL (normal range, 0.8 to 2 ng/mL). An ECG revealed prolonged and varying PR interval with atrial ectopics, subsequently converting to complete heart block. Because of continued bradycardic episodes, transcutaneous pacing was applied and a temporary pacemaker was inserted. Due to a high serum digoxin level and unavailability of digoxin Fab fragments, resin hemoperfusion was performed over a 4-hour period. Within 4 hours, the patient's vision improved and her nausea and vomiting resolved. Over the next 24 to 36 hours, her cardiac status improved with resolution of her heart block and a decrease in her digoxin level to 2.56 ng/mL. The patient was discharged 4 days after admission following normalization of her serum digoxin level and complete resolution of symptoms (Juneja et al, 2012).
h) CASE REPORT: A 26-year-old pregnant woman, at 21 weeks gestation, presented to the emergency department with burning pain, abdominal cramps, and lightheadedness approximately 2 hours after being injected intraperitoneally into the stomach with 1 mg digoxin. An ECG revealed sinus tachycardia, with a heart rate of 140. An initial digoxin level, obtained 2 hours post-injection, was 8.1 mg/dL and her potassium level was 3.4 mEq/L. Digibind was not administered and, 7 hours post-injection, her digoxin level decreased to 2.5 mg/dL. Following continued observation and resolution of symptoms, she was discharged 24 hours later. The outcome of the fetus was unknown (Mellesmoen & Gummin, 2015).

B) CARDIAC ARREST

1) WITH POISONING/EXPOSURE

a) Hypotension and cardiac arrest may occur. Peak cardiac effects generally occur 3 to 6 hours following digoxin overdosage and may persist for the ensuing 24 hours or longer (Caspi et al, 1997; Williams & Erickson, 1998).
b) CASE REPORT: Cardiac arrest was reported approximately 4 hours following an overdose of 10 mg digoxin in a 79-year-old man. Catecholamines were given during percutaneous cardiopulmonary bypass to maintain mean arterial pressure and the patient was placed on a respirator. Twelve days after the overdose the patient died from septic shock (Behringer et al, 1998).
c) CASE REPORT: Two weeks after undergoing an open-heart surgery, a 12-week-old girl with known cardiac disease (a double outlet right ventricle with a subaortic ventricular septal defect and a single coronary artery) presented in asystolic cardiac arrest secondary to an acute on chronic digoxin poisoning (125 mcg twice daily instead of 25 mcg twice daily; 750 mcg over a 3-day period instead of 150 mcg). Her digoxin level was 12.6 ng/mL. Following a successful resuscitation and the use of Digoxin-specific antibody fragments, she converted to normal sinus rhythm. She was discharged 6 days after the admission with full neurological recovery (Eyal et al, 2005).

C) VASCULAR DISORDER

1) WITH POISONING/EXPOSURE

a) NON-OCCLUSIVE MESENTERIC INFARCTION and refractory shock resulting in death have been reported following digoxin toxicity. A 79-year-old woman, with a serum digoxin level of 4.9 ng/mL, was hospitalized. On the fourth hospital day she developed abdominal pain, acidosis, refractory hypotension and absent bowel sounds; she died within a few hours. Autopsy showed massive small bowel infarction and histologic examination showed ischemic necrosis of the small bowel with no thrombosis in the superior mesenteric artery, left atrium or ventricle. The authors suggest that onset of non-occlusive mesenteric infarction may be delayed after cardiac glycoside toxicity and results from potent vasoconstrictor effects on the splanchnic arteries and arterioles (Guglielminotti et al, 2000).
b) CASE REPORT: An 84-year-old woman presented with signs and symptoms of digitalis intoxication (abdominal pain, nausea, vomiting, and confusion). Past medical history included hypertension and mild congestive heart failure. The patient was currently taking digitoxin at 0.07 mg/day. Abdominal examination revealed faint bowel sounds without signs of abdominal tenderness, distention, or rigidity. Laboratory analysis showed a decreased potassium level of 2.9 mmol/L and an elevated digitoxin plasma level of 32.3 ng/mL (normal range 13 to 25 ng/mL). Discontinuation of digitoxin therapy resulted in normalization of the potassium level, but the patient complained of worsening abdominal pain. An abdominal roentgenography and sonography showed signs of a paralytic ileus. The patient died approximately 48 hours later due to cardiovascular failure.

1) An autopsy revealed a diffusely dilated, intensely congested large and small intestine. The wall of the intestine was edematous and hemorrhagic. Histopathological examination showed pronounced edema of the submucosa and several areas of necrotic ulcerations and intramural bleeding, all of which was consistent with generalized non-occlusive gangrenous mesenteric ischemia (Weil et al, 2004).

c) CASE REPORT: A 76-year-old woman, on digitalis therapy, presented to the emergency department with a 3-day history of nausea and mild abdominal pain. Initial serum digoxin concentration was elevated at 6.04 ng/mL (normal range 0.8 to 2 ng/mL), indicating digitalis overdose. Three days after hospital admission, the patient developed sudden onset hematochezia with severe abdominal pain. A colonoscopy revealed hyperemia of the entire colon with generalized edema, and an abdominal CT scan demonstrated diffuse thickening of the descending colonic wall, all of which was consistent with a diagnosis of acute mesenteric ischemia. A mesenteric angiography revealed that, although the main branches of the superior mesenteric artery (SMA) and the inferior mesenteric artery (IMA) were intact, distal narrowings of the segmental and subsegmental branches were noted, with diminished intestinal mural perfusion, indicating non-occlusive mesenteric ischemia believed to be secondary to digitalis intoxication. Papaverine hydrochloride infusion was then initiated as treatment, but approximately 30 minutes later, the patient developed severe hypotension and the infusion was discontinued. The patient's condition deteriorated with the development of sepsis, hyperthermia, and leukocytosis. Despite aggressive supportive measures, including intravenous fluid replacement and antibiotic therapy, the patient was unresponsive and subsequently died (Kayahan et al, 2008).

3.5.3)

A) ANIMAL STUDIES

1) DYSRHYTHMIA

a) DOGS: In a canine model of acute digoxin toxicity, Meggs et al (1998) found that cardiac dysrhythmias (bradycardia in 2 dogs and multifocal PVS's in 1 dog) developed prior to hyperkalemia in all dogs, suggesting that hyperkalemia is separate from cardiac toxicity in the setting of acute digoxin poisoning (Meggs et al, 1998). Hyperkalemia and hypotension (which developed in 1 dog) resolved following Digibind(R) dosing.

Respiratory

3.6.2)

A) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Severe adult respiratory distress syndrome developed within 6 days in a 79-year-old man following an ingestion of 100 tablets of digoxin 0.1 mg. The patient was unable to be weaned from the respirator and died 12 days after the ingestion from septic shock (Behringer et al, 1998).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH POISONING/EXPOSURE

a) Lethargy, drowsiness, weakness, paresthesias, and headache may occur with digoxin toxicity (Morini et al, 2003; Song et al, 2001; Ekins & Watanabe, 1978; Smith & Willerson, 1971).
b) Extreme weakness and decreased muscle strength are commonly seen following cardiac glycoside intoxications (Cooke, 1993).
c) CASE REPORT: A misdiagnosis of depression was made in a 77-year-old woman about one month after the initiation of digitalis therapy (digoxin 0.5 mg/day). When therapy for depression was ineffective, the patient was transferred to another hospital where serum digoxin concentrations revealed a toxic level of digoxin (3.2 ng/mL). The patient improved over the next several days after stopping digoxin (Song et al, 2001).

B) CHOREOATHETOSIS

1) WITH POISONING/EXPOSURE

a) One case of digoxin-induced chorea has been reported (Wedzicha et al, 1984).

C) PSYCHOTIC DISORDER

1) WITH THERAPEUTIC USE

a) CASE REPORT: An 84-year-old woman previously controlled on 0.625 mg digoxin developed visual hallucinations without other symptoms of digitalis intoxication 2 days following the addition of a diuretic to her drug therapy (Closson, 1983).

2) WITH POISONING/EXPOSURE

a) Hallucinations, nightmares, paranoia, agitation, confusion, and delirium have been reported; these effects are common and usually resolve as the serum digitalis level declines (Song et al, 2001; Eisendrath & Sweeney, 1987; Rabinovitz et al, 1987; Carney et al, 1985; Closson, 1983).
b) Often, CNS signs will be the only presentation of digitalis toxicity, before cardiac or gastrointestinal symptoms (Cooke, 1993).
c) CASE REPORT: Psychosis was also noted in a 68-year-old woman with a serum digoxin level of 1.7 ng/mL (2.18 nmol/mL) (Carney et al, 1985).
d) CASE REPORT: Paranoid ideas with associated auditory hallucinations were reported with an elevated serum digoxin level of 5 ng/mL (6.4 nmol/mL), which resolved as the serum level returned to normal (Carney et al, 1985).

Gastrointestinal

3.8.2)

A) VOMITING

1) WITH POISONING/EXPOSURE

a) Nausea, vomiting and abdominal pain are early manifestations of acute and chronic toxicity (Juneja et al, 2012; Ekins & Watanabe, 1978; Gittelman et al, 1999). Persistent vomiting may occur with resultant dehydration.

B) VASCULAR INSUFFICIENCY OF INTESTINE

1) WITH POISONING/EXPOSURE

a) PEDIATRIC: A 2-month-old infant presented with a 12-hour history of drowsiness, vomiting, and mottled skin. Past medical history of the patient included cystic fibrosis and congenital heart disease characterized by ventricular septal defect, patent foramen ovale, and patent ductus arteriosus. Daily medications, prior to hospital admission, included pancreatic enzyme supplements, antibiotics, and digoxin (0.01 mg/kg/day). It was determined that the patient had been receiving digoxin at 0.1 mg/kg/day (a 10-fold dose) for approximately one week prior to admission. Digoxin intoxication was confirmed by a serum digoxin level of 4.5 ng/mL. Physical examination showed tachypnea, tachycardia, and a distended and tympanic abdomen with no bowel sounds. Administration of Digoxin-specific FAB antibody fragments resolved the patient's tachycardia, however she became lethargic and dehydrated with worsening respiratory distress, requiring mechanical ventilation.

1) An abdominal x-ray revealed signs suggesting necrotizing enterocolitis. A repeat abdominal x-ray suggested bowel perforation, however a laparotomy showed generalized small bowel ischemia and mild, bloodstained peritoneal fluid with no evidence of perforation. The patient's clinical condition continued to worsen over the next week and the patient developed partial wound dehiscence and evisceration with extensive bowel necrosis. A second exploratory operation revealed that the large bowel was healthy, but only 30 cm of small bowel appeared viable. On postoperative day 1 of the second surgery, the patient developed severe bradycardia, respiratory acidosis, and oliguria. Despite aggressive supportive measures, the patient died approximately 11 days after admission of hemorrhagic bowel necrosis, secondary to non-occlusive mesenteric ischemia (based on histologic evidence) (Morini et al, 2003).

Hematologic

3.13.2)

A) THROMBOCYTOPENIC DISORDER

1) WITH THERAPEUTIC USE

a) Digitoxin-induced severe thrombocytopenia (5,000/mm(3)) was reported in a patient with congestive heart failure associated with Sjogren's Syndrome. The platelet count recovered quickly following discontinuation of digitoxin, transfusion of platelet-rich plasma, and prednisolone and potassium treatment (Haro et al, 2000).

2) WITH POISONING/EXPOSURE

a) Digitoxin-induced severe thrombocytopenia (26,000/mm(3)), which was rapidly (within 16 h) reversed by digoxin specific antibodies has been reported (Hess et al, 1983).

Reproductive

3.20.1)

3.20.3)

A) PREGNANCY CATEGORY

1) Digoxin is FDA pregnancy category C (Prod Info LANOXIN(R) intravenous injection, intramuscular injection, 2013).

B) DIGOXIN

1) There are no adequate and well-controlled studies of digoxin in pregnant women. Animal studies have not been conducted (Prod Info LANOXIN(R) intravenous injection, intramuscular injection, 2013). Digoxin can be used in pregnancy, but may require dosage adjustments due to increased plasma volume, decreased protein binding, and increased renal excretion in the pregnant patient (Shotan et al, 1998). Digoxin has been used in pregnant women without apparent harm to the mother or fetus. The fetus is able to metabolize digoxin and excretes it in the bile. Low birth weight has been observed in infants of mothers receiving digitalis glycosides, presumably due to decreased gestational age and not due to intrauterine growth retardation (Witter et al, 1981; Weaver & Pearson, 1973; Rogers et al, 1972; Norris, 1961). In addition, adverse effects to the fetus have been found when the mother develops digitalis toxicity. Miscarriage was attributed to digitalis overdose in 1 case (Potondi, 1967). In another case, maternal digitalis toxicity was associated with ECG changes in the newborn and subsequent death, presumably due to intrauterine anoxia (Sherman & Locke, 1960). As it is unknown whether digoxin causes fetal harm when administered during pregnancy, it is recommended that the drug be administered in pregnant women only if clearly necessary (Prod Info LANOXIN(R) intravenous injection, intramuscular injection, 2013).

C) LACK OF EFFECT

1) There are no adequate and well-controlled studies of digoxin in pregnant women. Animal studies have not been conducted (Prod Info LANOXIN(R) intravenous injection, intramuscular injection, 2013). Congenital anomalies and perinatal problems have not been linked with cardiac glycoside use during pregnancy (Schardein, 1985).

3.20.4)

A) BREAST MILK

1) Two women receiving 0.25 mg digoxin during pregnancy continued therapy while breastfeeding. Starting on day 14, milk samples were collected after each feeding for a 24-hour period. Although detected in the milk samples, digoxin could not be detected in the plasma of either infant. Four to six hours after dosage, milk concentrations peaked at 0.96 and 0.61 ng/ml. Even at maternal toxicity levels, digoxin intake by infants would be less than 5% of the recommended dose. Digoxin was considered to be safe during breastfeeding (Loughnan, 1978).
2) Digoxin is excreted into breast milk and studies have shown that the milk-to-serum concentration ratio is approximately 0.6 to 0.9. However, the estimated exposure to digoxin in a nursing infant is far below the usual maintenance dose for an infant (Prod Info LANOXIN(R) intravenous injection, intramuscular injection, 2013). Therefore, this amount appears too low to be pharmacologically significant to the breastfeeding infant (Reinhardt et al, 1982; Berlin, 1981).

3.20.5)

A) LACK OF INFORMATION

1) No studies assessing the potential for digoxin to affect fertility have been conducted (Prod Info LANOXIN(R) intravenous injection, intramuscular injection, 2013).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS20830-75-5 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

B) IARC Carcinogenicity Ratings for CAS71-63-6 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

C) IARC Carcinogenicity Ratings for CAS630-60-4 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

D) IARC Carcinogenicity Ratings for CAS36-06-6 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.2)

A) Digoxin has been associated with chronic lymphocytic leukemia, but data are lacking to assess the potential carcinogenic activity of digoxin.

3.21.3)

A) LEUKEMIA

1) There was an association between past treatment with digoxin and incidence of chronic lymphocytic leukemia in Yorkshire (UK) (Cartwright et al, 1987). Digoxin is not considered a human carcinogen at the time of this review (Prod Info LANOXIN(R) oral tablets, 2011; Prod Info LANOXIN(R) IV, IM injection, 2011).

B) UTERINE CANCER

1) In a population-based study of postmenopausal Danish women aged 20 years and older, current use of digoxin was associated with a higher incidence of uterine cancer compared with nonusers. Registries identified 104,648 women with digoxin exposure with 249,652 person years (PY) of follow up for current exposure and 143,186 PY of follow up for prior exposure. During the study, uterine cancer, ovarian cancer, and cervical cancer were diagnosed in 8124, 7124, and 5001 women, respectively. Age-adjusted analysis revealed a higher incidence of uterine cancer in women with current digoxin use (n=350) compared with nonexposed women (risk ratio (RR), 1.48; 95% CI, 1.32 to 1.65). The incidence of uterine cancer increased significantly in women with a digoxin treatment duration of 36 months or longer compared with those using digoxin for 13 to 35 months (incidence rate ratio, 37 vs 71; p=0.0008); among all women using digoxin for at least 36 months (n=123), the overall RR for uterine cancer was 1.57 (1.31 to 1.89). The overall RR was not increased for ovarian or cervical cancers among digoxin users compared with nonusers. The incidence of uterine, ovarian, and cervical cancers were also not increased in other angina drug users compared with nonusers. For former digoxin users (starting 6 months after last digoxin prescription) there was a nonsignificant increase in uterine cancer (RR, 1.20; 95% CI, 0.99 to 1.45), while ovarian and cervical cancer incidence rates did not increase (Biggar et al, 2012)

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor serial serum digoxin concentrations and serum electrolytes every hour, until patient is improved and digoxin concentrations are clearly declining towards therapeutic. False positive digoxin concentrations have been reported in patients with pregnancy, liver disease, and hypothermia.
B) Monitor renal function.
C) For acute cardiac glycoside exposure, serum potassium (hyperkalemia) is the best marker of toxicity. Serum potassium should be monitored every 60 minutes following any potentially significant acute exposure to a cardiac glycoside. Serum potassium is NOT predictive of toxicity for chronic cardiac glycoside toxicity.
D) Institute continuous cardiac monitoring and obtain serial ECG's.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) SERUM POTASSIUM: For acute cardiac glycoside exposure, serum potassium (hyperkalemia) is the best marker of toxicity. Serum potassium should be monitored every 60 minutes following any potentially significant acute exposure to a cardiac glycoside. Serum potassium is NOT predictive of toxicity for chronic cardiac glycoside toxicity; in these patients hyper- or hypokalemia may occur

a) HYPERKALEMIA may be profound (Smith & Willerson, 1971; Citrin et al, 1972; Hastreiter et al, 1984; Antman & Smith, 1985) and life threatening. The degree of hyperkalemia has been correlated with mortality in digitoxin overdose (Bismuth et al, 1973).
b) HYPOKALEMIA: Due to concurrent diuretic administration can result in digitalis toxicity even with therapeutic plasma levels (Gomez-Arnau et al, 1982). May also occur in chronic digitalis poisoning in the absence of diuretic use.

2) SERUM DIGOXIN: Monitor serial serum digoxin concentrations and serum electrolytes every hour, until the patient is improved and digoxin concentrations are clearly declining towards therapeutic. False positive digoxin concentrations have been reported in patients with pregnancy, liver disease, and hypothermia.
3) Monitor renal function.
4) GLUCOSE: Hypoglycemia (43 mg/dL) was noted 13 hours after administration of digoxin immune Fab in a one-week-old infant, despite intravenous dextrose administration (42 mg/kg/min) (Kaufman et al, 1990).

B) SPECIFIC AGENT

1) DIGOXIN RANGE OF LEVELS: Therapeutic range 0.5 to 2 nanograms/mL (0.64 to 2.56 nmol/L). Patients have survived with levels as high as 48 nanograms/mL (61.49 nmol/L) (Springer et al, 1986). Deaths have been reported with levels as low as 3.5 nanograms/mL (4.48 nmol/L) (Baselt & Cravey, 1989). Toxicity from acute overdose in most patients is seen above 10 nanograms/mL (12.8 nmoL/L).

a) In overdose, the distribution phase may be prolonged, therefore, serum digoxin levels may not be meaningful until approximately 6 hours post-ingestion (Smith et al, 1993).

2) DIGOXIN SAMPLING TIME: Digoxin toxicity may erroneously be reported in a patient if serum digoxin concentrations are sampled prior to completion of drug distribution. Due to digoxin pharmacokinetics, serum samples should not be drawn within 6 hours of the previous dose, unless toxicity or overdose is strongly suspected (Williamson et al, 1998). Digoxin levels are not meaningful following administration of Digoxin-specific FAB, depending on the assay used. False elevations can be noted if the "free digoxin assay" is not used or if excess FAB has been administered.
3) DIGOXIN NORMAL LEVELS AND TOXICITY: Cardiotoxicity has been reported with serum digoxin concentrations in the therapeutic range. Patients with digoxin-induced cardiac toxicity and therapeutic serum digoxin concentrations showed significant increases in the calcium to potassium ratio and arterial pH (Sonnenblick et al, 1983).
4) DIGOXIN MORTALITY: A retrospective study examining the relationship between digoxin serum levels and outcome 4 weeks after the level demonstrated the following mortality rates (Ordog et al, 1987):

Digoxin level		Number Patients	Number Deaths	4 week mortality rate
0*	ng/mL	1000	20	2%
0-1	ng/mL	1366	26	2%
1.1-2	ng/mL	3184	159	5%
2.1-4	ng/mL	409	36	8.6%
4.1-6	ng/mL	40	3	7.5%
>6	ng/mL	11	5	50%
~ *Admitted medical patients not on digoxin who served as matched-pair controls.

5) DIGOXIN AND THE PEDIATRIC PATIENT: Pediatric patients appear to be more resistant to the cardiotoxic effects of digoxin than adults at comparable serum levels (Pearce et al, 1980; Lewander et al, 1986; Springer et al, 1986; Harris et al, 1981).

a) Children excrete digoxin more rapidly than older patients (Krasula et al, 1972). Koren et al (1988) reported elevation in serum digoxin concentration in 11 of 15 profoundly sick, digitalized infants and children long after cessation of therapy (Koren et al, 1988).

6) DIGOXIN AND EXERCISE: One study evaluating the influence of everyday exercise on steady-state digoxin concentrations found a significant difference in concentrations comparing baseline, one hour of immobilization prior to exercise (increase 30%), one hour of exercise (decrease 26.8%), and one hour of immobilization after exercise (increase 36.6%) (Hall et al, 1989).
7) DIGOXIN STEADY STATE: Tayeb et al (1988) using calculated digoxin clearance values were able to accurately predict serum steady state digoxin levels (r = 0.96) (Tayeb et al, 1988).
8) DIGITOXIN: Therapeutic range of DIGITOXIN or DIGITALIS LEAF is 18 to 22 nanograms/mL (23 to 28.18 nmol/L). Toxicity in most patients is above 25 nanograms/mL (32 nmol/L).

C) LABORATORY INTERFERENCE

1) DIGOXIN IMMUNE FAB: Serum levels may rise precipitously after digoxin immune fab is administered, as antibody-bound digoxin is also measured. Serum digoxin concentration measurements can be clinically misleading when digoxin Fab fragments are present because the digoxin immune Fab interferes with digitalis immunoassay measurements (Personal Communication, 1989).
2) A number of studies have addressed this problem. Several immunoassays appear to be able to quantitate free serum digoxin in the presence of Fab. The use of ultrafiltration (which removes Fab and Fab-bound digoxin) with some assays allows the measurement of both total (bound and unbound) and free digoxin (Banner, 1989; (Hansell, 1989; Ujhelyi et al, 1990) .
3) An evaluation of 28 assay methods showed 7 methods that could accurately measure free digoxin in the presence of digoxin immune Fab. These assays were (Hansell, 1989):

1) Abbott PEG
2) Baxter Healthcare STRATUS
3) Becton Dickinson ARIA HT
4) Becton Dickinson ARIA II
5) Becton Dickinson Solid Phase
6) Leeco Diagnostics
7) Nuclear Medical Laboratories

4) In other studies, assays tested included FPIA-TDX Digoxin II-Abbott Laboratories, EMIT-Syva, RIA-Quantitope ULTRA-FIPA (ultrafiltration with FIPA), and STRATUS-Baxter Dade. EMIT, STRATUS, and ULTRA-FPIA were able to quantitate free total serum digoxin concentrations in the presence of Fab. Ultra-FPIA was the most accurate and reliable assay (Ujhelyi et al, 1992; Ujhelyi et al, 1990).
5) DLIS: Digoxin-like immunoreactive substance (DLIS) is an endogenous natriuretic substance(s) found in the blood of neonates, seriously ill older infants (Spiehler et al, 1985), pregnant women (Gilson et al, 1997), and patients with a variety of disease states including renal (Graves et al, 1983; Greenway & Nanji, 1985) Shild, 1985) and hepatic failure, heart failure, diabetes and hypertension (Tzou et al, 1997; Martinka et al, 1998). Its role, if any, is not known.

a) DLIS cross react with several immunologic assay methods used for digoxin, leading to elevation of levels and potential confusion in the interpretation of results (Luke & Dasgupta, 1997). Apparent levels of DLIS as high as 3.7 ng/mL (Karboski et al, 1988) and 0.3 to 1.1 ng/mL (Tzou et al, 1997) have been reported. A microparticle enzyme immunoassay (MEIA) method appears to have a very low cross-reactivity with DLIS compared with the fluorescence polarization immunoassay (FPIA) (Crossey & Dasgupta, 1997).
b) Morris et al (1990) have reported the cross reactivity to DLIS demonstrated by 10 commercial assay methods. The Diagnostic Products Corporation "Coat-a-Count" RIA and the Syva EMIT column run on a Cobas MIRA by Roche produced the least interference (Morris et al, 1990).
c) Baseline serum digoxin concentrations should be measured prior to administration of digoxin in neonates.
d) DLISs are highly protein bound. Because of their high protein binding and the poor protein binding of digoxin, either measuring digoxin concentrations in protein-free ultrafiltrate or monitoring free digoxin concentrations can eliminate the positive and negative cross-interference of the DLIS (Dasgupta, 2002).

6) OTHER SUBSTANCES: Ingestion of exogenous digoxin-like immunoreactive substances, including spironolactone and its active metabolite, canrenone, and traditional Chinese medicines (Chan Su, Siberian Ginseng, and Dan Shen) may also cause positive and negative cross-interference with immunoassays used to measure serum digoxin concentrations (Dasgupta, 2002).
7) OLEANDER GLYCOSIDES: Glycosides found in oleander may cross-react with antibodies found in most radioimmunoassay kits and result in digoxin being reported as present (Haynes et al, 1985; Shumaik et al, 1988).

4.1.4)

A) OTHER

1) ECG

a) Institute continuous cardiac monitoring and obtain serial ECG's.

Methods

1) Determination of cardiac glycosides in serum is available in most hospitals by radioimmunoassay, which is a reliable technique (Smith et al, 1969; Williamson et al, 1998; Lecointre et al, 2001). An EMIT(R) homogeneous enzyme immunoassay and fluorescent polarization methodology (Abbott TDx system (R)) are also used. Clinical studies show excellent correlation between these methods and RIA.

a) A modified EMIT 2000 digoxin assay for determining very low digoxin plasma concentrations was developed on the Cobas Mira plus analyzer. Detection and quantification limits of 0.02 and 0.08 ng/mL, respectively, were reported. Good correlation between this modified EMIT assay and RIA was shown (Radembino et al, 1999).

2) Plasma levels obtained soon after an overdose may not accurately reflect toxicity, as the drug may still be in the distribution phase, which normally takes approximately 6 hours from the last dose (Williamson et al, 1998).
3) It may take several hours to obtain laboratory results and the diagnosis should be considered on clinical grounds.
4) DRUG-LABORATORY INTERFERENCE -

a) In the presence of Digoxin immune Fab, positive interference may be expected due to competition with assay capture antibodies. Interference with most methods is concentration-dependent, following a linear relationship. Interference by these large molecules may be minimized by ultrafiltration. McMillin et al (2002) reported the following assay methods which had minimal interference: TDx, AxSYM, Synchron, and CEDIA methods. In the presence of Fab products, ultrafiltration appears to be the optimal strategy for accurate determination of free digoxin concentrations (McMillin et al, 2002).
b) Steimer et al (1999) reported falsely low readings in a common assay for digoxin (AxSYM MEIA) due to negative cross-reactivity from canrenone (an active metabolite of potassium canrenoate) and spironolactone. A case of digoxin toxicity resulted from elevated digoxin dosing guided by falsely low laboratory readings (Steimer et al, 1999).
c) Assays that employ mouse monoclonal antibody reagents may result in falsely elevated serum digoxin levels in patients who have human anti-mouse antibody in their serum which interferes with the agent (Ingels et al, 1999). Interference in assays with newer reagents does not result with this antibody.

1) Serum levels may rise precipitously after digoxin immune fab is administered, as antibody-bound digoxin is also measured. Serum digoxin concentration measurements can be clinically misleading when digoxin Fab fragments are present because the Fab fragments interfere with digitalis immunoassay measurements (Personal Communication, 1989).
2) A number of studies have addressed this problem. Several immunoassays appear to be able to quantitate free serum digoxin in the presence of Fab. The use of ultrafiltration (which removes Fab and Fab-bound digoxin) with some assays allows the measurement of both total (bound and unbound) and free digoxin (Banner, 1989; (Hansell, 1989) Ujelyi, 1990; (Jortani et al, 1999). Analysis of ultrafiltrate by immunoassay which does not have matrix bias appears to be the most accurate method in measuring unbound digoxin in presence of antidote.

a) An evaluation of 28 assay methods showed 7 methods that could accurately measure free digoxin in the presence of Fab fragments. These assays were (Hansell, 1989):

1) Abbott PEG
2) Baxter Healthcare STRATUS
3) Becton Dickinson ARIA HT
4) Becton Dickinson ARIA II
5) Becton Dickinson Solid Phase
6) Leeco Diagnostics
7) Nuclear Medical Laboratories

b) In other studies, assays tested included FPIA-TDX Digoxin II-Abbott Laboratories, EMIT-Syva, RIA-Quantitope ULTRA-FIPA (ultrafiltration with FIPA), and STRATUS-Baxter Dade. EMIT, STRATUS, and ULTRA-FPIA were able to quantitate free total serum digoxin concentrations in the presence of Fab. Ultra-FPIA was the most accurate and reliable assay (Ujhelyi et al, 1992; Ujhelyi et al, 1990).
c) In one case report of digoxin intoxication, 3 immunoassay techniques produced very different values. The serum digoxin levels were 9.44 ng/mL (on admission), 6.46 ng/mL, and 2.63 ng/mL using the enzyme multiplied immunoassay (EMIT) reagents (Cobas Mira autoanalyzer), the fluorescence polarization immunoassay (FPIA/FLx technique [Digoxin II assay]), and the microparticle enzyme immunoassay (MEIA/AxSYM technique [Digoxin II assay]), respectively. The digoxin level of 5.46 ng/mL was obtained using the liquid chromatography-electrospray-mass spectrometry (LC-ES-MS) method. The authors concluded that MEIA/AxSYM result was greatly underestimated and these findings reinforce the doubt on the reliability of this technique for detecting digoxin overdose (Tribut et al, 2005).
d) Banner et al (1989) compared two immunoassays for digoxin in the presence of Fab fragments; the Abbott TDx(R) and the Dade Stratus(R) methods. Serum spiked with digoxin 0 to 50 ng/mL and Fab 0 to 3 mcg/mL was assayed by TDx with and without ultrafiltration, and by Stratus. TDx was found to accurately quantitate total serum digoxin concentrations (i.e., both bound and non-bound by Fab), whereas Stratus measured only non-bound drug. After ultrafiltration, the TDx assay measured non-Fab-bound digoxin levels. Banner et al (1992) confirmed their previous findings in a similar follow-up study (Banner et al, 1989; Banner et al, 1992).

3) The effect of digoxin Fab antibody on the measurement of total and free digitoxin by fluorescence polarization and chemiluminescent immunoassay was reported. Interference in the measurement of TOTAL digitoxin concentration by both laboratory tests was seen in vitro, with falsely lowered total digitoxin levels. Monitoring of FREE digitoxin concentrations revealed no interference in vitro and was found to be accurate when measured by either assay (Dasgupta et al, 1999).
4) DLIS: Digoxin-like immunoreactive substance (DLIS) is an endogenous natriuretic substance(s) found in the blood of neonates, seriously ill older infants (Spiehler et al, 1985), pregnant women, and patients with a variety of disease states including renal (Graves et al, 1983; Greenway & Nanji, 1985) Shild, 1985) and hepatic failure, heart failure, and hypertension. Its role, if any is not known.

a) DLIS cross reacts with several immunologic assay methods used for digoxin, leading to elevation of levels and potential confusion in the interpretation of results. Apparent levels of DLIS as high as 3.7 ng/mL have been reported (Karboski et al, 1988).
b) Morris et al (1990) have reported the cross reactivity to DLIS demonstrated by 10 commercial assay methods. The Diagnostic Products Corporation "Coat-a-Count" RIA and the Syva EMIT column run on a Cobas MIRA by Roche produced the least interference (Morris et al, 1990).
c) Ingestion of exogenous digoxin-like immunoreactive substances, including spironolactone and its metabolite, canrenone, and traditional Chinese medicines (Chan Su, Siberian Ginseng, and Dan Shen) may also cause positive and negative cross-interference with immunoassays used to measure serum digoxin concentrations (Dasgupta, 2002).
d) DLISs are highly protein bound. Because of their high protein binding and the poor protein binding of digoxin, either measuring digoxin concentrations in protein-free ultrafiltrate or monitoring free digoxin concentrations can eliminate the positive and negative cross-interference of the DLIS (Dasgupta, 2002).

5) OLEANDER GLYCOSIDES: Glycosides found in oleander may cross-react with antibodies found in most radioimmunoassay kits and result in digoxin being reported as present (Haynes et al, 1985; Shumaik et al, 1988).

a) There is no correlation of the serum level to toxicity in these cases (Osterloh, 1988).

6) The Abbott TDx analyzer used with Digoxin II reagents, may qualitatively identify other cardiac glycosides as well, but the concentration relationship is not linear (Cheung et al, 1989).
7) POSTMORTEM LEVELS: Levels may increase and persist postmortem. In one series of 27 digitalized children, digoxin levels obtained within the first 24 hours after death were 6.5 (SD 1.1) nmol/L higher than calculated digoxin levels at the time of death (Koren et al, 1989). This finding may be due to redistribution from fat or muscle and/or increased DLIS secretion postmortem (Vorpahl & Coe, 1978; Holt & Benstead, 1975) Koren, 1989; Thomas, 1979).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Admit all patients, who develop dysrhythmias, heart block, severe vomiting, or who require digoxin immune Fab treatment, to an ICU setting. Admit patients to a monitored setting if they have digoxin concentrations that are not clearly declining during 8 hours of observation.

6.3.1.2) HOME CRITERIA/ORAL

A) Healthy asymptomatic children who are not chronically taking cardiac glycosides or other antiarrhythmic drugs may be observed at home after accidental ingestions of less than a digitalizing dose.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients who have only GI symptoms and a clearly decreasing serum digoxin concentration can be discharged after a minimum of 8 hours of observation.

Monitoring

Oral Exposure

6.5.1)

A) TRIAGE/DECONTAMINATION

1) SUMMARY - All patients with a history of unintentional ingestion of more than a digitalizing dose or intentional overdose of any amount of cardiac glycoside should be referred to a hospital for evaluation and treatment.

B) CHILDREN

1) Children with a history of unintentional ingestion of more than a digitalizing dose of a cardiac glycoside should be referred to a health care facility for gastric lavage, activated charcoal, and observation for a minimum of 8 hours. Prehospital administration of activated charcoal should be considered in these patients if it is readily available.

C) EMESIS/NOT RECOMMENDED

1) Emesis may enhance vagal stimulation and exacerbate bradycardia or heart block, and is not recommended for cardiac glycoside ingestion.

D) ACTIVATED CHARCOAL

1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.2)

A) SUMMARY

1) CHILDREN

a) Children with a history of accidental ingestion of more than a digitalizing dose of a cardiac glycoside presenting to a health care facility should receive activated charcoal. Consider gastric lavage in recent ingestions.

2) ADULTS

a) Adults with a history of accidental ingestion or intentional overdose of any amount of a cardiac glycoside should be referred to a hospital for evaluation and administration of activated charcoal. Consider gastric lavage in recent ingestions.

B) MULTIPLE DOSE ACTIVATED CHARCOAL

1) While digoxin immune Fab fragments are the preferred treatment for severe or life-threatening cardiac glycoside intoxication, multiple dose activated charcoal may be useful in situations in which Fab fragments are not available. Multiple dose activated charcoal has been shown to enhance elimination of digoxin and/or digitoxin in animal models (Chyka et al, 1995), volunteers (Park et al, 1985; Reissell & Manninen, 1982; Lalonde et al, 1985), and overdose cases (Pond et al, 1981; Blody et al, 1985) (Lake et al, 84) (Critchley & Critchley, 1997; Ibanez et al, 1995). It has not been shown to affect outcome after overdose.
2) Multiple dose activated charcoal should be considered in patients with potentially life threatening poisoning when digoxin immune Fab fragments are not readily available.
3) MULTIPLE DOSE ACTIVATED CHARCOAL

a) ADULT DOSE: Optimal dose not established. After an initial dose of 50 to 100 grams of activated charcoal, subsequent doses may be administered every 1, 2 or 4 hours at a dose equivalent to 12.5 grams/hour (Vale et al, 1999), do not exceed: 0.5 g/kg charcoal every 2 hours (Ghannoum & Gosselin, 2013; Mauro et al, 1994). There is some evidence that smaller more frequent doses are more effective at enhancing drug elimination than larger less frequent doses (Park et al, 1983; Ilkhanipour et al, 1992). PEDIATRIC DOSE: Optimal dose not established. After an initial dose of 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) (Chyka & Seger, 1997), subsequent doses may be administered every 1, 2 or 4 hours (Vale et al, 1999) in a dose equivalent to 6.25 grams/hour in children 1 to 12 years old.
b) Activated charcoal should be continued until the patient's clinical and laboratory parameters, including drug concentrations if available, are improving (Vale et al, 1999). The patient should be frequently assessed for the ability to protect the airway and evidence of decreased peristalsis or intestinal obstruction.
c) Use of cathartics has not been shown to increase drug elimination and may increase the likelihood of vomiting. Routine coadministration of a cathartic is NOT recommended (Vale et al, 1999).
d) AGENTS AMENABLE TO MDAC THERAPY: The following properties of a drug that are likely to allow MDAC therapy to be effective include: small volume of distribution, low protein binding, prolonged half-life, low intrinsic clearance, and a nonionized state at physiologic pH (Chyka, 1995; Ghannoum & Gosselin, 2013).
e) Vomiting is a common adverse effect; antiemetics may be necessary.
f) CONTRAINDICATIONS: Absolute contraindications include an unprotected airway, intestinal obstruction, a gastrointestinal tract that is not intact and agents that may increase the risk of aspiration (eg, hydrocarbons). Relative contraindications include decreased peristalsis (eg, decreased bowel sounds, abdominal distention, ileus, severe constipation) (Vale et al, 1999; Mauro et al, 1994).
g) COMPLICATIONS: Include constipation, intestinal bleeding, bowel obstruction, appendicitis, charcoal bezoars, and aspiration which may be complicated by acute respiratory failure, adult respiratory distress syndrome or bronchiolitis obliterans (Ghannoum & Gosselin, 2013; Ray et al, 1988; Atkinson et al, 1992; Gomez et al, 1994; Mizutani et al, 1991; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Mina et al, 2002; Harsch, 1986; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002).

C) GASTRIC LAVAGE

1) CAUTION: Gastric lavage may enhance vagal stimulation and exacerbate bradycardia or heart block.
2) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

3) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

4) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

5) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

6) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

7) PRECAUTIONS

a) Cardiac arrest has been noted during gastric lavage, believed to be secondary to a vagal response in a patient with preexisting nodal rhythm (Hobson & Zettner, 1973). Some authors suggest pretreatment with atropine before lavage (Sharff & Bayer, 1982), but this is NOT recommended.
b) An intravenous line should be established and atropine should be readily available for administration if bradycardia occurs during the lavage procedure.

D) WHOLE BOWEL IRRIGATION (WBI)

1) May be useful after large ingestions.

a) WHOLE BOWEL IRRIGATION/INDICATIONS: Whole bowel irrigation with a polyethylene glycol balanced electrolyte solution appears to be a safe means of gastrointestinal decontamination. It is particularly useful when sustained release or enteric coated formulations, substances not adsorbed by activated charcoal, or substances known to form concretions or bezoars are involved in the overdose.

1) Volunteer studies have shown significant decreases in the bioavailability of ingested drugs after whole bowel irrigation (Tenenbein et al, 1987; Kirshenbaum et al, 1989; Smith et al, 1991). There are no controlled clinical trials evaluating the efficacy of whole bowel irrigation in overdose.

b) CONTRAINDICATIONS: This procedure should not be used in patients who are currently or are at risk for rapidly becoming obtunded, comatose, or seizing until the airway is secured by endotracheal intubation. Whole bowel irrigation should not be used in patients with bowel obstruction, bowel perforation, megacolon, ileus, uncontrolled vomiting, significant gastrointestinal bleeding, hemodynamic instability or inability to protect the airway (Tenenbein et al, 1987).
c) ADMINISTRATION: Polyethylene glycol balanced electrolyte solution (e.g. Colyte(R), Golytely(R)) is taken orally or by nasogastric tube. The patient should be seated and/or the head of the bed elevated to at least a 45 degree angle (Tenenbein et al, 1987). Optimum dose not established. ADULT: 2 liters initially followed by 1.5 to 2 liters per hour. CHILDREN 6 to 12 years: 1000 milliliters/hour. CHILDREN 9 months to 6 years: 500 milliliters/hour. Continue until rectal effluent is clear and there is no radiographic evidence of toxin in the gastrointestinal tract.
d) ADVERSE EFFECTS: Include nausea, vomiting, abdominal cramping, and bloating. Fluid and electrolyte status should be monitored, although severe fluid and electrolyte abnormalities have not been reported, minor electrolyte abnormalities may develop. Prolonged periods of irrigation may produce a mild metabolic acidosis. Patients with compromised airway protection are at risk for aspiration.

6.5.3)

A) SUPPORT

1) Digoxin and potassium concentrations should be followed; continuous ECG monitoring is also indicated. Therapy should be guided by the occurrence of life threatening dysrhythmia, significant cardiac compromise or severe hyperkalemia rather than by digoxin concentration alone. In the absence of major clinical signs/symptoms, an absolute digoxin concentration of greater than 10 nanomoles/liter (6 hours after last dose) is an indication for the use of digoxin Fab fragments (Dawson & Whyte, 2001).
2) Indications for digoxin immune Fab include manifestations of severe toxicity (ventricular dysrhythmias, progressive bradyarrhythmias, 2nd or 3rd degree heart block not responsive to atropine), hyperkalemia (greater than 5.0 mEq/dL in acute overdose), significant risk of cardiac arrest, ingestion of greater than 10 mg in an adult or greater than 4 mg in a child, level greater than 10 ng/mL post-distribution, progressive increase in potassium concentration postingestion, and unresponsiveness to immediately available conventional therapy.

a) Bosse & Pope (1994) reported a case of a 38-year-old man who took an overdose of digoxin and other medications on 3 separate occasions as a suicide attempt. Digibind(R) was administered successfully on each occasion. The third overdose produced a Wenckebach AV block with a ventricular rate of 38 beats/minute which was successfully treated with atropine followed by 7 vials (total 266 mg) of Digibind(R). No allergic manifestations to Digibind(R) occurred after administration for the 3 separate overdose events (Bosse & Pope, 1994).
b) CASE REPORT: A 6-month-old child developed AV junctional tachycardia (heart rate of 300 bpm) after receiving 3 doses of digoxin intravenously (0.16 mg, 0.08 mg, and 0.08 mg). One minute after receiving Digoxin Immune FAB, given as an intravenous bolus dose of 14.2 mg, the AV junctional tachycardia converted to a regular sinus rhythm at a heart rate of 140 bpm (Husby et al, 2003).

3) Antiarrhythmics that may be useful include atropine, phenytoin, and lidocaine.
4) Bradycardia unresponsive to atropine or phenytoin may be treated with external or pacing.
5) If digoxin immune Fab is unavailable, hyperkalemia may be treated with insulin, dextrose, and bicarbonate; magnesium sulfate may be effective for digoxin-induced dysrhythmias.
6) CHRONIC POISONING: When the patient is hemodynamically stable, many common manifestations, such as first-degree heart block, bradycardia, and ventricular ectopy, can be treated with only temporary withdrawal of the medication and close monitoring.

B) MONITORING OF PATIENT

1) Monitor serial serum digoxin concentrations and serum electrolytes every hour, until patient is improved and digoxin concentrations are clearly declining towards therapeutic. False positive digoxin concentrations have been reported in patients with pregnancy, liver disease, and hypothermia.
2) Monitor renal function.
3) For acute cardiac glycoside exposure, serum potassium (hyperkalemia) is the best marker of toxicity. Serum potassium should be monitored every 60 minutes following any potentially significant acute exposure to a cardiac glycoside. Serum potassium is NOT predictive of toxicity for chronic cardiac glycoside toxicity.
4) Institute continuous cardiac monitoring and obtain serial ECG's.

C) DIGOXIN IMMUNE FAB (OVINE)

1) Digoxin immune Fab is available as DigiFab(R), which is made using keyhole-limpet hemocyanin as the large carrier protein.
2) INDICATIONS (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012; Bayer, 1991a):

a) Manifestations of severe toxicity: ventricular dysrhythmias, progressive bradyarrhythmias, 2nd or 3rd degree heart block not responsive to atropine, refractory hypotension.
b) Hyperkalemia (greater than 5.0 mEq/L) in acute overdose.
c) Significant risk of cardiac arrest: ingestion of greater than 10 mg in an adult, greater than 4 mg in a child, level greater than 10 ng/mL post-distribution (generally 6 to 8 hours postingestion), progressive increase in potassium concentration postingestion.
d) Unresponsiveness to immediately available conventional therapy.
e) Digoxin serum levels of greater than 10 ng/mL by 6 hours after the overdose, even in asymptomatic patients, is considered an indication for digoxin immune FAB by some authors (Bailey et al, 1997).

3) DOSING

a) GENERAL DOSING INFORMATION

1) Dosing varies according to the amount of digoxin ingested. In cases, of acute exposure of an unknown amount, 20 vials (800 mg) of DigiFab(R) is adequate in both adults and children to treat most life-threatening ingestions. In clinical testing, the average dose was 10 vials (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).
2) The six-vial dose (240 mg) is usually adequate to reverse most cases of chronic toxicity in an adult and in children weighing at least 20 kg (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).
3) Doses of 10 or more vials are more likely to elicit a febrile reaction (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).
4) When determining the dose for DIGOXIN IMMUNE FAB, the following guidelines should be considered (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012):

a) Erroneous calculations may result from inaccurate estimates of the amount of digitalis ingested or absorbed or from non-steady state serum digitalis concentrations.
b) Inaccurate serum digitalis concentration measurements are a possible source of error. Most serum digoxin assay kits are designed to measure values less than 5 nanograms/milliliter (ng/mL). Dilution of samples is required to obtain accurate measures above 5 ng/mL.
c) Dosage calculations are based on a steady-state volume of distribution of approximately 5 liters per kilogram for digoxin (0.5 liters/kilogram for digitoxin) to convert serum digitalis concentrations to the amount of digitalis in the body. The conversion is based on the principle that body load equals drug steady-state serum concentration multiplied by volume of distribution. These volumes are population averages and vary widely among individuals. Many patients may require higher doses for complete neutralization. Doses should ordinarily be rounded up to the next whole vial.
d) If toxicity has not adequately reversed after several hours or appears to recur, readministration of DIGOXIN IMMUNE FAB at a dose guided by clinical judgment may be required.
e) Failure to respond to DIGOXIN IMMUNE FAB raises the possibility that the clinical problem is not caused by digitalis intoxication. If there is no response to an adequate dose of DIGOXIN IMMUNE FAB, the diagnosis of digitalis toxicity should be reconsidered.

b) ACUTE INGESTION OF UNKNOWN AMOUNT OF DIGOXIN

1) ADULTS AND CHILDREN

a) DOSAGE SUMMARY

1) Initial dose, 20 vials (800 mg); OR
2) Initial dose, 10 vials with close monitoring of clinical response and repeat dosing of 10 vials as required (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012)

b) DOSING INFORMATION

1) Administer digoxin immune Fab by intravenous infusion over 30 minutes using an in-line 0.22 micron membrane filter. If cardiac arrest is imminent, give as a bolus injection (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).
2) Each vial of DigiFab(R) (40 mg purified digoxin-specific Fab fragments) will bind approximately 0.5 digoxin (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).
3) PEDIATRIC: Since infants and small children can have much smaller dosage requirements, it is recommended that the 40-mg vial be reconstituted as directed and administered with a tuberculin syringe. For very small doses, a reconstituted vial can be diluted with 36-mL of sterile isotonic saline to achieve a concentration of 1 mg/mL. In children it is important to monitor for volume overload (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012).

c) ACUTE INGESTION OF KNOWN AMOUNT OF DIGOXIN

1) ADULTS AND CHILDREN

a) Calculations Based on Estimated Amount of Digoxin Ingested (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012):

DIGIFAB(R) (milligrams of digoxin)x F*
Dose      =    ---------------------------
(vials)        0.5 mg of digitalis bound/vial

1) F* = bioavailability
2) F* = 0.8 for 0.25 mg tablets
3) F* = 1 for 0.2 mg Lanoxicaps

d) SINGLE INGESTION OF KNOWN AMOUNT

1) ADULTS AND CHILDREN

a) Approximate Dose of DigiFab(R) for Reversal of a Single Large Digoxin Overdose (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012):

Number of Digoxin Tablets* or Capsules** Ingested	DigiFab(R) Dose (vials)
25	10
50	20
75	30
100	40
150	60
200	80

1) * = 0.25 milligram (mg) tablets with 80% bioavailability
2) ** = 0.2 mg Lanoxicaps with 100% bioavailability

e) CHRONIC DIGOXIN INGESTION TOXICITY

1) ADULTS AND OLDER/LARGER CHILDREN

a) DOSAGE SUMMARY

1) Adults and older/larger pediatric patients in acute distress and without known serum digoxin concentration (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012):

1) Initial dose, 6 vials (240 mg)

b) CALCULATIONS BASED ON STEADY-STATE DIGOXIN CONCENTRATIONS

DIGIFAB(R)  Serum digoxin (ng/mL) x weight (kg)
Dose      =    ---------------------------
(vials)                        100

1) Estimated DigiFab(R) dose (in number of vials) per Steady-State serum Digoxin Concentration (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012):

a) PATIENT WEIGHT = 40 kg

Serum Digoxin (ng/mL)	DIGIFAB(R) Dose (vials)
1	0.5
2	1
4	2
8	3
12	5
16	7
20	8

b) PATIENT WEIGHT = 60 kg

Serum Digoxin (ng/mL)	DIGIFAB(R) Dose (vials)
1	0.5
2	1
4	3
8	5
12	7
16	10
20	12

c) PATIENT WEIGHT = 70 kg

Serum Digoxin (ng/mL)	DIGIFAB(R) Dose (vials)
1	1
2	2
4	3
8	6
12	9
16	11
20	14

d) PATIENT WEIGHT = 80 kg

Serum Digoxin (ng/mL)	DIGIFAB(R) Dose (vials)
1	1
2	2
4	3
8	7
12	10
16	13
20	16

e) PATIENT WEIGHT = 100 kg

Serum Digoxin (ng/mL)	DIGIFAB(R) Dose (vials)
1	1
2	2
4	4
8	8
12	12
16	16
20	20

2) INFANTS/SMALL CHILDREN

a) Infants and Small Children Dose Estimates of DIGOXIN IMMUNE FAB (in mg) from Steady-State Serum Digoxin Concentration (Prod Info DigiFab(R) intravenous injection lyophilized powder for solution, 2012):

1) FORMULA: Dose (in mg) = (Dose [in # of vials]) (40 mg/vial)
2) PATIENT WEIGHT = 1 kg

Serum Digoxin (ng/mL)	DIGIFAB(R) Dose
1	0.4 mg*
2	1 mg*
4	1.5 mg*
8	3 mg*
12	5 mg
16	6.5 mg
20	8 mg

a) * = Dilution of reconstituted vial to 1 mg/mL may be desirable

3) PATIENT WEIGHT = 3 kg

Serum Digoxin (ng/mL)	DIGIFAB(R) Dose
1	1 mg*
2	2.5 mg*
4	5 mg
8	10 mg
12	14 mg
16	19 mg
20	24 mg

a) * = Dilution of reconstituted vial to 1 mg/mL may be desirable

4) PATIENT WEIGHT = 5 kg

Serum Digoxin (ng/mL)	DIGIFAB(R) Dose
1	2 mg*
2	4 mg
4	8 mg
8	16 mg
12	24 mg
16	32 mg
20	40 mg

a) * = Dilution of reconstituted vial to 1 mg/mL may be desirable

5) PATIENT WEIGHT = 10 kg

Serum Digoxin (ng/mL)	DIGIFAB(R) Dose
1	4 mg
2	8 mg
4	16 mg
8	32 mg
12	48 mg
16	64 mg
20	80 mg

6) PATIENT WEIGHT = 20 kg

Serum Digoxin (ng/mL)	DIGIFAB(R) Dose
1	8 mg
2	16 mg
4	32 mg
8	64 mg
12	96 mg
16	128 mg
20	160 mg

3) CALCULATIONS BASED ON STEADY-STATE DIGITOXIN CONCENTRATION

DIGIFAB(R)  Serum digitoxin (ng/mL) x weight (kg)
Dose      =    ---------------------------
(vials)                        1000

4) PRECAUTIONS

a) SERUM DIGOXIN LEVELS: Free digoxin rebound peaks about 3 to 24 hours following Fab administration in patients with normal renal function and then a slow steady decline in free digoxin occurs at a rate dependent on Fab and renal and nonrenal routes of elimination (Ujhelyi et al, 1993).
b) RENAL FAILURE

1) Dialysis is probably first-line therapy to restore potassium to normal levels in an anephric patient. Digoxin and the digoxin Fab complex are believed to be poorly dialyzable due to molecular weights in excess of 500 as well as due to extensive tissue binding of digoxin and the large volume of distribution of digoxin (Clifton et al, 1989).
2) In an anephric patient, one might predict failure to clear the Fab/digoxin complex. The reticuloendothelial system has been suggested as a mechanism to eliminate the complex (Prod Info, 1991). The elimination half-life has been reported to be delayed in these patients (Colucci et al, 1989; Erdmann et al, 1989; Nuwayhid & Johnson, 1989).
3) Allen et al (1991) reported that free serum digoxin levels gradually rose from 0 to 2.9 ng/mL 44 to 97 hours after Fab treatment in 4 digoxin toxic patients with renal failure (Allen et al, 1991).
4) CASE REPORT: A newborn, with acute renal failure and digoxin toxicity was treated with FAB 6 mg intravenously. In view of severe metabolic acidosis and high potassium and creatinine plasma concentrations, peritoneal dialysis was initiated. Laboratory analysis revealed a very low level of free digoxin in the plasma and dialysate and low concentrations of total digoxin in the dialysate, indicating poor elimination of the digoxin-FAB complex through peritoneal dialysis. Plasma creatinine did not improve, but potassium concentration returned to normal, sodium levels increased, and the acidosis was corrected (Berkovitch et al, 1994).
5) Ujhelyi et al (1993) reported that the time to peak free digoxin rebound occurred 127 +/- 40 hours in end-stage renal failure patients as compared to 55 +/- 28 hours in other patients. The level of the maximum free digoxin rebound was similar between patients with and without end-stage renal failure (1.79 +/- 0.96 compared with 1.61 +/- 1.41 nmol/mL, respectively) (Ujhelyi et al, 1993).

a) Renal dysfunction appears to slow the elimination of total digoxin following Fab therapy and the rebound in free digoxin may be affected by renal function. Monitoring of free digoxin following administration of Fab is recommended in order to monitor additional Fab dosing, confirm possible rebound toxicity, or guide the reinitiation of digoxin therapy.

6) PLASMA EXCHANGE for the removal of digoxin-specific antibody fragments in anuric renal failure is reported. In patients with normal renal function, Fab-digoxin complexes are eliminated via glomerular filtration. Zdunek et al (2000) concluded in a case report that optimal timing of plasma exchange should be within the first 3 hours after FAB administration (to parallel the peak of bound digoxin levels). Plasma exchange was found to be efficacious for removing digoxin-Fab complexes (preventing rebound digoxin toxicity) but was not efficacious for improving total digoxin clearance due to the large apparent volume of distribution of digoxin (Zdunek et al, 2000).

a) In another case, Chillet et al (2002) also reported the use of plasma exchange in an anuric renal failure patient with digoxin toxicity; a waiting period ranging between 24 and 40 hours, corresponding to the usual return to free blood digoxin after Fab injection in renal failure, was followed. Free serum digoxin was reported to decrease from 9.86 mcg/L at the second plasma exchange to 1.67 mcg/L after the third plasma exchange (Chillet et al, 2002).

c) RECURRENT DIGITALIS TOXICITY: Commonly reported (Sinclair et al, 1989; Hursting et al, 1987; Hewett et al, 1989; Kurowski et al, 1992). More likely to occur in patients receiving less than the estimated required DigiFab(R) dose. Onset generally within 3 days of initial treatment, but may occur as late as 11 days post treatment; reported in 3% of 717 patients in one study (Hickey et al, 1991). If free (unbound) digoxin level is not available, the decision to retreat with Fab should be made on clinical grounds.

1) Mehta et al (2002) described a patient who presented with atrial fibrillation with a ventricular response of 44 beats/min in the setting of chronic digoxin intoxication (acute renal failure, serum digoxin 16 ng/dL). ECG returned to baseline after 8 vials of digoxin specific Fab fragments. After 24 hours ECG showed atrial fibrillation with bigemini, which was felt to represent rebound digoxin toxicity. Serum for free digoxin concentration was not obtained, the patient continued to deteriorate hemodynamically and clinically and died (Mehta et al, 2002).

5) ADVERSE EFFECTS

a) HYPOKALEMIA: May occur precipitously after administration of digoxin immune Fab. Serum potassium concentration should be closely monitored (Antman et al, 1990).
b) ALLERGIC REACTIONS: Rare; reported in less than 1% of patients. Skin reactions most common; others rare (Smith, 1989; Antman et al, 1990; Hickey et al, 1991) .

1) Hickey et al (1991) reported a 0.8% incidence of allergic responses during treatment with Fab in a total Fab treatment population of 717 patients (Hickey et al, 1991).

c) CONGESTIVE HEART FAILURE: May be precipitated in patients who require digitalis to maintain cardiac output who are then given digoxin immune Fab (Antman et al, 1990).
d) APNEA: Occurred transiently in one neonate during Fab infusion (Antman, 1991).
e) HYPOGLYCEMIA: Reported in one neonate 13 hours post-Fab infusion (Kaufman et al, 1990).

6) EFFICACY

a) Successfully used in the management of severe acute digoxin and digitoxin poisoning in children (Zucker et al, 1982; Murphy et al, 1982; Rossi et al, 1984; Woolf et al, 1991; Woolf et al, 1992), in premature infants (Presti et al, 1985; Menget et al, 1989), in a neonate (Kaufman et al, 1990), and adults (Smith et al, 1976; Leikin et al, 1985; Schaumann et al, 1986; Smolarz et al, 1985; Spiegel & Marchlinski, 1985) Wenger, 1985; (Kurowski et al, 1992). Also effective in treating patients with lanatoside C intoxication (Hess et al, 1979), and oleander poisoning (Shumaik et al, 1988).
b) In a trial involving 150 patients treated with Fab fragments, 75% of patients showed an initial response to treatment within 60 minutes, while complete reversal of digoxin toxicity was usually evident within 4 hours of administration (Antman et al, 1990). In addition, a total of 80% of patients responded completely to treatment and 10% improved substantially.
c) In a study involving 717 patients, 50% had a complete response to treatment with Fab fragments, 24% a partial response and 12% had no response (Hickey et al, 1991a).
d) Digibind(R) and Digitab(R) were compared in the reversal of digoxin-induced cardiac toxicity in the rat model. The two drugs appeared to be equally effective in the reversal of the PTQ ((PTQ = PR interval(sec) x T score)/QTc(sec)) and hyperkalemia (Dart et al, 1995).

7) PHARMACOKINETICS: Digoxin-specific Fab, which is eliminated via renal and nonrenal routes, has a volume of distribution of approximately 0.4 L/kg and an elimination half-life of 16 to 20 hours. Elimination half-lives may be increased up to 10-fold in patients with renal dysfunction, while volume of distribution is unaffected. Digoxin-toxic patients with preserved renal function have systemic clearance of digoxin-specific Fab of about 0.32 mL/min/kg while renal failure decreases Fab clearance by up to 75%. Anephric patients may have Fab in their serum for 2 to 3 weeks following its administration (Ujhelyi & Robert, 1995).

a) Pharmacokinetic demise of total digoxin after digoxin-specific Fab dosing follows that of Fab.

D) HYPERKALEMIA

1) OVERVIEW: May be life-threatening. Caused by poisoning of Na-K pump by glycoside, so that intracellular potassium becomes extracellular; there is not increased total body potassium. Digoxin immune Fab is first-line treatment; if unavailable, insulin, glucose, and bicarbonate may be given (and will lower potassium level for up to 12 hours). Calcium increases cardiac effects of glycosides, and may precipitate dysrhythmias and should be given with great caution, if at all. Kayexalate(R) is not indicated (lowers total body potassium). Use caution with beta-2 agonist inhalers due to prodysrhythmic effects.
2) CAUTION: Fab fragments and bicarbonate/insulin/glucose should not be used simultaneously because severe hypokalemia may result.
3) DIGOXIN IMMUNE FAB: Indications include hyperkalemia (generally greater than 5 mEq/L) or progressively increasing levels postingestion. First-line treatment, if available. Restores Na-K pump function and rapidly reverses hyperkalemia. (NOTE: See above for doses).

a) CASE REPORT: A 6-month-old child developed hyperkalemia, with a peak serum potassium concentration of 7.8 mmol/L after receiving three doses of digoxin intravenously (0.16 mg, 0.08mg, and 0.08 mg). Twenty minutes after receiving Digoxin immune FAB, the patient's serum potassium concentration normalized (4.5 mmol/L) (Husby et al, 2003).

4) CASE SERIES: A review of cases from a single poison control center from 2002 to 2014 was conducted, identifying 358 cases of digoxin exposure. Of these 358 cases, 210 were treated at a healthcare facility, where 42 patients were identified as hyperkalemic following digoxin exposure. Sixteen of the 42 patients were not treated with digoxin specific Fab fragments, with 1 death recorded. The median digoxin levels in the survivors and in the 1 death were 3.1 ng/mL and 4 ng/mL, respectively, with median potassium levels of 6 and 6.3 mEq/L, respectively. Of the 26 hyperkalemic patients who received treatment with Fab fragments, 2 deaths occurred. The median digoxin levels in the survivors and in each of the 2 fatalities were 4.3, 6, and 3.1 ng/mL, respectively, with potassium levels of 6.1, 6.1, and 6.3 mEq/L, respectively. Based on these results, the outcome appeared to be similar regardless of therapy; however, limitations to this study include lower serum digoxin levels in the patients not treated with Fab fragments, indicating less severe digoxin toxicity, and the possibility of pseudohyperkalemia (Emswiler et al, 2015).
5) SODIUM BICARBONATE

a) INDICATIONS: Life-threatening hyperkalemia (K greater than 6.5 mEq/L) if digoxin immune Fab not readily available. Use with insulin/D50.
b) DOSE: ADULT: 2 ampules (44 mEq/ampule) IV. CHILD: 1 to 2 mEq/L.
c) MECHANISM: Causes intracellular shift of potassium.

6) DEXTROSE/INSULIN

a) INDICATIONS: Life-threatening hyperkalemia (K greater than 6.5 mEq/L) if digoxin immune Fab not readily available. Use with sodium bicarbonate.
b) DOSE: ADULT: Regular insulin 5-10 units IV push, D50W 2 amps (100 mL) IV push. CHILD: Regular insulin 0.2 units/kg IV push, D50W 1 mL/kg IV push.

7) ECG MONITORING: Indicated continuously during hyperkalemia treatment.
8) CALCIUM: The effects of cardiac glycosides on the myocardium are increased by elevated serum calcium levels. Administration of parenteral calcium to a digitalized patient should be done with extreme caution, to avoid the possible precipitation of cardiac dysrhythmias. If necessary, calcium should be administered slowly and in small quantities (Hansten & Horn, 1989; Zucchero & Hogan, 1990).

a) A retrospective review of medical records was conducted from 1989 to 2005 at a tertiary care medical center in Boston, Massachusetts, identifying 159 patients with digoxin toxicity. Of the 159 patients with digoxin toxicity, 23 patients were given intravenous calcium as treatment. There were no life-threatening dysrhythmias that occurred within 4 hours following calcium administration. Five of the 23 patients (22%) who received calcium died during their hospitalization, with 3 of the 5 deaths (60%) attributed to digoxin toxicity and not associated with calcium administration. In comparison, 27 of the 136 patients (20%) who did not receive calcium died during their hospitalization, with 15 of the 27 deaths (56%) attributed to digoxin toxicity. A multivariate controlled analysis showed a non-significant decrease in mortality in patients who received calcium (OR 0.76; 95% CI 0.24 to 2.5) (Levine et al, 2009).

E) ATROPINE

1) INDICATIONS: Useful in the management of bradycardia, and varying degrees of heart block due to the digitalis-induced effects of enhanced vagal tone on SA node rhythmicity and on conduction through the AV node (Smith & Willerson, 1971; Duke, 1972).
2) DOSE

a) ATROPINE/DOSE

1) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
2) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.

a) There is no minimum dose (de Caen et al, 2015).
b) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).

F) LIDOCAINE

1) INDICATIONS: Useful in the management of ventricular tachydysrhythmias, PVCs, and bigeminy. Lidocaine does not improve conduction through the AV node. Digoxin immune Fab is preferred therapy for dysrhythmias.
2) LIDOCAINE/DOSE

a) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.

1) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).

b) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).

3) LIDOCAINE/MAJOR ADVERSE REACTIONS

a) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).

4) LIDOCAINE/MONITORING PARAMETERS

a) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

G) PHENYTOIN

1) INDICATIONS: Useful as a third-line agent in the management of digitalis-induced ventricular dysrhythmias (PVCs, ventricular tachycardia and bigeminy) and improves conduction through the AV node (Damato et al, 1970; Helfant et al, 1967). Digoxin immune Fab is preferred therapy for dysrhythmias.
2) DOSE

a) IMPAIRED AV CONDUCTION: Low dose phenytoin (ADULT: 25 mg/dose IV at 1 to 2 hour intervals; CHILD: 0.5 to 1.0 mg/kg/dose IV at 1 to 2 hour intervals) appears to improve AV conduction (Rumack et al, 1974).
b) VENTRICULAR DYSRHYTHMIAS: Larger doses needed: LOADING DOSE FOR ADULTS AND CHILDREN: Administer 15 mg/kg up to 1.0 g IV not to exceed a rate of 0.5 mg/kg/minute. MAINTENANCE DOSE: ADULT: Administer 2 mg/kg IV every 12 hours as needed; CHILD: Administer 2 mg/kg every 8 hours as needed.

3) MONITOR SERUM PHENYTOIN LEVELS just prior to initiating and during maintenance therapy to assure therapeutic levels of 10 to 20 mcg/mL (39.64 to 79.28 nanomoles/liter). Monitor ECG carefully.

H) MAGNESIUM

1) Magnesium has been reported to reverse digoxin-induced tachydysrhythmias (Davey, 2002; French et al, 1984; Neff et al, 1972; Reisdorff et al, 1986). It should be used extremely cautiously if at all in the presence of renal failure or bradycardia. Digoxin immune Fab is preferred therapy for dysrhythmias.
2) DOSE: ADULT: 20 mL of 20% solution over 20 minutes by slow infusion. Infusion should be stopped if patient vomits, becomes hypotensive, develops worsening heart block, or loses deep tendon reflexes. Magnesium levels in serum should be followed.
3) CASE REPORT: Kinlay & Buckley (1995) report a case of an 83-year-old woman with digoxin toxicity, ventricular tachycardia and a minimally elevated serum magnesium who was treated with IV magnesium sulfate. 20 mmol of IV magnesium sulfate resulted in a more stable junctional rhythm with bigeminy (Kinlay & Buckley, 1995).

I) AMIODARONE

1) Successfully used in 2 patients with dysrhythmias resistant to lidocaine, phenytoin, and cardioversion (Maheswaran et al, 1983; Nicholls et al, 1985).
2) LOADING DOSE: ADULT: 150 mg infused over 15 minutes.
3) MAINTENANCE DOSE: ADULT: 1 mg/min over the first 6 hours, followed by 0.5 mg/min over the following 18 hours.

J) EMERGENCY CARDIAC PACEMAKER

1) INDICATIONS: Digoxin immune Fab fragments are the treatment of choice for dysrhythmias secondary to cardiac glycoside toxicity. Pacemaker (external or transvenous) use should be considered in severe bradycardia and/or slow ventricular rate due to second or high-degree AV block that fails to respond to atropine and/or phenytoin when digoxin Fab are not available (Citrin et al, 1973; Bismuth et al, 1977; Schwartz, 1977; Taboulet et al, 1993).
2) ACUTE OVERDOSE: Taboulet et al (1993) studied 51 patients with cardiac glycoside overdoses who were treated with cardiac pacing and/or Fab fragments. Results showed an 8% failure rate with Fab in the prevention of life-threatening dysrhythmias and a 23% failure with cardiac pacing. In this study pacing was associated with a high rate of complications (14 out of 39, 5 of them fatal) including 6 cases of pacing-induced dysrhythmias, 6 pacing failures and 2 cases of sepsis (Taboulet et al, 1993)
3) CHRONIC POISONING: In a retrospective study, the safety of transvenous temporary cardiac pacing (TCP) was evaluated in patients (n=70; 74 +/- 12 years) with unintentional digoxin-related symptomatic bradyarrhythmias. Of those that received TCP for various arrhythmias (sinus arrest with junctional bradyarrhythmias, atrial fibrillation with a slow ventricular rate, and high-degree AV block), no major dysrhythmias or mortality were reported. In the comparison group (no TCP) two deaths were reported due to ventricular tachyarrhythmias (Chen et al, 2004).

a) The authors concluded that TCP is safe for individuals experiencing chronic digoxin overdose associated with symptomatic bradycardia, but concluded that the findings may not be applicable following an acute exposure (ie, attempted suicide). Following acute exposure, patients may be at greater risk to develop more frequent ventricular responses, and the use of TCP in the overdrive mode may increase the risk of ventricular tachyarrhythmias resulting in potentially serious complications (Chen et al, 2004).

K) CARDIOPULMONARY BYPASS OPERATION

1) Percutaneous cardiopulmonary bypass has been used for therapy resistant cardiac arrest due to digoxin overdose. Catecholamines may be needed during bypass to maintain arterial pressure. This method may provide hemodynamic support and sufficient tissue perfusion to allow neutralization by digoxin immune Fab in patients with cardiac arrest due to massive cardiac glycoside overdoses (Behringer et al, 1998).

L) DRUG THERAPY FINDING

1) Other agents such as sodium salts of EDTA, lactones, heparin, propranolol, or calcium channel blockers are of questionable value following acute massive overdose.

M) EXPERIMENTAL THERAPY

1) HYPERINSULINEMIA-EUGLYCEMIA (HIE) THERAPY: In a rat model of acute digoxin toxicity, HIE infusion delayed abnormalities in cardiac conduction and improved rat survival. At this time, HIE therapy should still be considered experimental for cardiac glycoside poisoning and is not recommended in humans until more data is available (Oubaassine et al, 2006).

Enhanced Elimination

1) DIGITOXIN elimination appears to be enhanced by the serial administration of cholestyramine, 4 g orally every 6 hours (Pieroni & Fisher, 1981; Cady et al, 1979). In one patient with chronic toxicity cholestyramine effect was delayed for 48 hours and appeared limited to the gut; serum clearance was not increased.
2) Cholestyramine was found to have minimal effect on DIGOXIN absorption and excretion in man (Hall et al, 1977); but was reported to decrease the serum digoxin half-life from 75.5 hours to 19.9 hours in a 94-year-old man with chronic digoxin toxicity and renal insufficiency (Henderson & Solomon, 1988).

1) COLESTIPOL, a steroid binding resin, has been claimed to enhance the elimination of digoxin and digitoxin (Kilgore & Lehmann) (Bazzano & Bazzano, 1972).

1) Furosemide-induced forced diuresis has been reported to enhance excretion by some authors (Rotmensch et al, 1978; Koren & Klein, 1988), while others have shown no effect (Semple et al, 1975; Brown et al, 1976).

1) Hemodialysis is ineffective in removing cardiac glycosides but may assist in restoring serum potassium to normal levels.

1) SUMMARY: Plain, charcoal, and immobilized antidigoxin antibody hemoperfusion have all been used in digoxin and digitoxin overdose. None of these techniques have proven utility in these ingestions.
2) PLAIN HEMOPERFUSION

a) DIGOXIN: Not useful; removes less than 1% of total ingested dose (Warren & Fanestil, 1979).
b) DIGITOXIN: Increased clearance in one study (n=11) using Amberlite XAD 4 resin column. Removal rate increased 8.6 times with 1 column and 14 times with 2, with corresponding reductions in serum level of 32% and 59% (Mathiew, 1983).

3) B2-MG ADSORPTION COLUMN

a) Digoxin intoxication was successfully managed by hemoperfusion with specific columns for B2-microglobulin-adsorption (Lixelle(TM)) in a maintenance hemodialysis patient with renal failure. The direct hemoperfusion column was connected to the arterial end of a hemodialyzer. Serum digoxin concentration decreased from 6.00 to 2.31 ng/mL, with marked improvement in the patient's GI symptoms (level rebounded to 3.59 ng/mL). Six days later the same therapy was repeated, with further improvement of digoxin serum concentration from 3.59 to 1.70 ng/mL (Kaneko et al, 2001).

1) Tsuruoka et al (2001) also reported successful lowering of digoxin concentrations in 8 hemodialysis patients following hemoperfusion with a column for B2-microglobulin-adsorption. This column appears to selectively adsorb digoxin and it possesses a higher capacity for digoxin removal than activated charcoal in vitro (Tsuruoka et al, 2001).

4) CHARCOAL HEMOPERFUSION

a) DIGOXIN: Used in a few cases (Smiley et al, 1978) (Marbury, 1979); (Gibson, 1990); (Suzuki, 1988). Pharmacokinetic data suggest the procedure is not useful (Freed, 1979).
b) DIGITOXIN: One case report of 50% removal of a 10 mg dose in 8 hours (Gilfrich, 1979). Half-life reduced from 145 to 20 hours.

5) IMMOBILIZED ANTIDIGOXIN ANTIBODY HEMOPERFUSION

a) TECHNIQUE: Plasma flows across small columns containing antidigoxin antibodies bound to polyacrolein microspheres in agarose microspheres.
b) RESULTS: One human trial (Savin, 1987) reported 87 mL/min plasma clearance in 10 digoxin toxic patients. One animal study (Brizgys, 1989) reported 5% to 20% removal of total dose without measurable effect on serum digoxin level.
c) CONCLUSION: Not recommended at present.

6) RESIN HEMOPERFUSION

a) CASE REPORT: A 30-year-old woman developed persistent vomiting, diplopia, blurred and yellow vision, and intermittent episodes of bradycardia with hypotension after ingesting 70 0.25-mg digoxin tablets (total dose 17.5 mg). An initial serum digoxin level was 12.63 ng/mL (normal range 0.8 to 2 ng/mL). An ECG revealed prolonged and varying PR interval with atrial ectopics, subsequently converting to complete heart block. Because of continued bradycardic episodes, transcutaneous pacing was applied and a temporary pacemaker was inserted. Due to a high serum digoxin level and unavailability of digoxin Fab fragments, resin hemoperfusion was performed over a 4-hour period. Within 4 hours, the patient's vision improved and her nausea and vomiting resolved. Over the next 24 to 36 hours, her cardiac status improved with resolution of her heart block and a decrease in her digoxin level to 2.56 ng/mL. The patient was discharged 4 days after admission following normalization of her serum digoxin level and complete resolution of symptoms (Juneja et al, 2012).

1) NOT INDICATED: Multiple plasma exchange did not significantly alter digoxin kinetics and had a slight effect on digitoxin. The estimated fraction of the body burden removed by one exchange was 5.5% for digitoxin and 1.2% for digoxin (Keller et al, 1985).

1) Used to treat a patient with chronic renal failure who developed hyperkalemia and complete heart block associated with a digoxin level of 3.2 ng/mL (4.1 nanomoles/liter). Hyperkalemia corrected within 6 hours and heart block resolved 12 hours after continuous arteriovenous hemofiltration (Lai et al, 1986).

1) Peritoneal dialysis was initiated in a newborn with acute renal failure and digoxin toxicity treated with intravenous FAB. Peritoneal dialysis was ineffective in removing the digoxin-FAB complex but was helpful in restoring serum potassium to normal levels and correcting the acidosis (Berkovitch et al, 1994).
2) CASE REPORT: Caspi et al (1997) reported no significant enhanced clearance of digoxin with an intensive peritoneal dialysis schedule in a 64-year-old man with chronic renal failure and digoxin toxicity (Caspi et al, 1997).

Abstracts

Case Reports

1) FAB: One case of a patient in renal failure whose free serum digoxin concentration rose fourfold 5 days after Fab administration has been reported. The authors attributed this rise to possible Fab fragment/digoxin complex dissociation after ruling out other possible causes. They suggest that patients with renal failure who are treated with Fab fragments should have free serum digoxin concentration monitored (Schneider et al, 1991).
2) FAB: Kurowski et al (1992) reported that a massive overdose of digitoxin (35 mg) was successfully treated with FAB therapy (Kurowski et al, 1992). FAB treatment was initiated 11 hours postingestion when the total serum concentration was 535 mmol/L. The patient required 2 additional infusions at 21 and 37 hours postingestion because of recurrence of toxic symptoms.

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) SPECIFIC DISEASE STATE

1) HEART FAILURE

a) IV/IM: For rapid digitalization, give loading dose of 8 to 12 mcg/kg IV/IM; administer one-half of total loading dose initially, followed by one-fourth of the total loading dose every 6 to 8 hours for 2 doses. For maintenance dosing, the recommended dose is 2.4 to 3.6 mcg/kg IV/IM once daily; may increase dose every 2 weeks based on clinical response, drug levels, and toxicity (Prod Info LANOXIN(R) intravenous injection, intramuscular injection, 2013).
b) ORAL TABLETS: For rapid digitalization, the total loading dose is 10 to 15 mcg/kg orally; administer one-half of total loading dose initially, followed by one-fourth of the total loading dose every 6 to 8 hours twice. For daily maintenance doses or for gradual digitalization, the recommended dose 3.4 to 5.1 mcg/kg orally once daily; titrate every 2 weeks (Prod Info LANOXIN(R) oral tablets, 2013).
c) ORAL SOLUTION: For maintenance dosing, the recommended oral dose is 3 to 4.5 mcg/kg/day (Prod Info digoxin oral solution, 2011).
d) ORAL CAPSULES: Lanoxicap(R) digoxin capsules have been discontinued by the manufacturer. Divided daily dosing is presently recommended for patients requiring a daily dose of 300 micrograms (mcg) or greater, for patients with a previous history of digitalis toxicity, for patients considered likely to become toxic, and for patients in whom compliance is not a problem. For rapid digitalization, give loading dose of 8 to 12 mcg/kg IV/IM; administer one-half of total loading dose initially, followed by one-fourth of the total loading dose every 6 to 8 hours for 2 doses. For maintenance dosing, the recommended dose is 50 to 350 mcg once daily, titrating every 2 weeks (Prod Info LANOXICAPS(R) oral capsules, 2005).

2) ATRIAL FIBRILLATION

a) The American College of Cardiology/American Heart Association/European Society of Cardiology guidelines recommend a loading dose of 0.25 mg IV/orally every 2 hours up to 1.5 mg MAX. The recommended maintenance dose is 0.125 to 0.375 mg orally daily OR 0.125 to 0.25 mg IV daily (guideline dosing)(Fuster et al, 2006).
b) IV/IM: For rapid digitalization, give loading dose of 8 to 12 mcg/kg IV/IM; administer one-half of total loading dose initially, followed by one-fourth of the total loading dose every 6 to 8 hours for 2 doses. For maintenance dose, give 2.4 to 3.6 mcg/kg IV/IM once daily; may increase dose every 2 weeks based on clinical response, drug levels, and toxicity (manufacturer dosing) (Prod Info LANOXIN(R) intravenous injection, intramuscular injection, 2013).
c) ORAL TABLETS: For rapid digitalization, give total loading dose of 10 to 15 mcg/kg ORALLY; administer one-half of total loading dose initially, followed by one-fourth of the total loading dose every 4 to 8 hours twice. For daily maintenance doses or for gradual digitalization, give 3.4 to 5.1 mcg/kg ORALLY once daily; titrate every 2 weeks (manufacturer dosing) (Prod Info LANOXIN(R) oral tablets, 2012).

7.2.2)

A) LOADING DOSE ("RAPID DIGITALIZATION")

1) Generally used only in urgent situations (eg, treating arrhythmias or acute congestive heart failure). The total digitalizing dose is usually given over 16 to 24 hours as 3 divided doses every 6 to 8 hours (Hobbins et al, 1981).
2) Oral doses should be 25% greater than IV doses. A slower digitalization can be accomplished by initiating an appropriate maintenance dose (Prod Info LANOXIN(R) intravenous injection, intramuscular injection, 2013; Jain & Vaidyanathan, 2009; Park, 1986).

B) MAINTENANCE DOSE

1) Maintenance doses are approximately 25% of digitalizing doses. Twice-daily dosing (over once-daily dosing) is recommended in younger children (10 years of age and younger). This minimizes the potential risk of toxic peak concentrations and subtherapeutic trough levels (Jain & Vaidyanathan, 2009; Bakir & Bilgic, 1994; Park, 1986). In a study in children (n=30), statistically significant differences were noted in peak levels for once-daily dosing (2.3 +/- 0.8 nanograms (ng)/mL) compared with twice-daily dosing (1.6 +/- 0.7 ng/mL) (Bakir & Bilgic, 1994).

C) SPECIFIC DISEASE STATE

1) HEART FAILURE

a) IV/IM: For rapid digitalization, administer one-half of total loading dose initially, followed by one-fourth of the total loading dose every 6 to 8 hours for 2 doses. Total IV/IM loading dose: (premature) 15 to 25 mcg/kg; (full-term) 20 to 30 mcg/kg; (1 to 24 months) 30 to 50 mcg/kg; (2 to 5 years) 25 to 35 mcg/kg; (5 to 10 years) 15 to 30 mcg/kg; (over 10 years) 8 to 12 mcg/kg (Prod Info LANOXIN(R) intravenous injection, intramuscular injection, 2013)
b) ORAL SOLUTION: For loading dose, first dose: give half the total loading dose; subsequent doses: as clinically indicated, give additional fractions of the total loading dose at 4- to 8-hour intervals; TOTAL ORAL loading dose: (premature) 20 to 30 mcg/kg; (full term) 25 to 35 mcg/kg; (1 to 24 months) 35 to 60 mcg/kg; (2 to 5 years) 30 to 45 mcg/kg; (5 to 10 years) 20 to 35 mcg/kg; (over 10 years) 10 to 15 mcg/kg (Prod Info digoxin oral solution, 2011).

1) For maintenance dosing, recommended oral doses are (premature) 2.3 to 3.9 mcg/kg twice daily; (full term) 3.8 to 5.6 mcg/kg twice daily; (1 to 24 months) 5.6 to 9.4 mcg/kg twice daily; (2 to 5 years) 4.7 to 6.6 mcg/kg twice daily; (5 to 10 years) 2.8 to 5.6 mcg/kg twice daily; (over 10 years) 3 to 4.5 mcg/kg once daily (Prod Info digoxin oral solution, 2011).

c) ORAL TABLETS:

1) 5 to 10 years: For rapid digitalization, the total loading dose is 20 to 45 mcg/kg orally; administer one-half of total loading dose initially, followed by one-fourth of the total loading dose every 6 to 8 hours twice. For daily maintenance doses or for gradual digitalization, give 3.2 to 6.4 mcg/kg orally twice daily (Prod Info LANOXIN(R) oral tablets, 2013).
2) 11 years and older: For rapid digitalization, the total loading dose is 10 to 15 mcg/kg orally; administer one-half of total loading dose initially, followed by one-fourth of the total loading dose every 6 to 8 hours twice. For daily maintenance doses or for gradual digitalization, give 3.4 to 5.1 mcg/kg orally once daily; titrate every 2 weeks (Prod Info LANOXIN(R) oral tablets, 2013)

d) ORAL CAPSULES:

1) Lanoxicap(R) digoxin capsules have been discontinued by the manufacturer. For rapid digitalization, the recommended doses were 25 to 35 mcg/kg (ages, 2 to 5 years), 15 to 30 mcg/kg (ages, 5 to 10 years), and 8 to 12 mcg/kg (ages over 10 years). The maintenance dose was 25% to 35% of the oral or IV digitalizing dose (Prod Info LANOXICAPS(R) oral capsules, 2005).

2) SUPRAVENTRICULAR TACHYCARDIA (SVT)

a) Higher oral maintenance doses (up to 15 mcg/kg/day) may be necessary to control the ventricular rate in infants and children with SVT (Pfammatter & Stocker, 1998; Luedtke et al, 1997).

Minimum Lethal Exposure

1) Adult patients with normal hearts rarely develop life threatening toxicity with less than 5 milligrams in an acute ingestion. Fatal ingestions resulting in cardiac arrest are usually greater than 10 milligrams in healthy adults or greater than 4 mg in a previously healthy child (Prod Info LANOXICAPS(R) oral capsules, 2005).
2) Survival has been reported in adults following acute ingestion of 20 milligrams digoxin.
3) There is insufficient controlled data in the literature to accurately determine the minimum toxic or lethal dose in humans.

Maximum Tolerated Exposure

1) Acute single ingestions of greater than 2 to 3 milligrams are generally associated with manifestations of toxicity. Acute ingestion of less than 2 to 3 mg in a patient on chronic (daily) digoxin therapy may result in toxicity.
2) A child with a normal heart can probably tolerate two milligrams orally without cardiac toxicity, but should be observed in a hospital for at least 8 hours.
3) A 36-year-old man survived a massive overdose of digitoxin (35 mg) following treatment with FAB fragments. Prior to FAB therapy, the total serum concentration was 535 nanomoles/liter at 11 hours postingestion (Kurowski et al, 1992).
4) Two weeks after undergoing an open-heart surgery, a 12-week-old girl with known cardiac disease (a double outlet right ventricle with a subaortic ventricular septal defect and a single coronary artery) presented in asystolic cardiac arrest secondary to an acute on chronic digoxin poisoning (125 mcg twice daily instead of 25 mcg twice daily; 750 mcg over a 3-day period instead of 150 mcg). Her digoxin level was 12.6 ng/mL. Following a successful resuscitation and the use of Digoxin-specific antibody fragments, she converted to normal sinus rhythm. She was discharged 6 days after the admission with full neurological recovery (Eyal et al, 2005).
5) CASE REPORT: A 30-year-old woman developed persistent vomiting, diplopia, blurred and yellow vision, and intermittent episodes of bradycardia with hypotension after ingesting 70 0.25-mg digoxin tablets (total dose 17.5 mg). An initial serum digoxin level was 12.63 ng/mL (normal range 0.8 to 2 ng/mL). An ECG revealed prolonged and varying PR interval with atrial ectopics, subsequently converting to complete heart block. Following resin hemoperfusion, the patient gradually recovered and was discharged on hospital day 4 (Juneja et al, 2012).
6) CASE REPORT: A 26-year-old pregnant woman, at 21 weeks gestation, presented to the emergency department with burning pain, abdominal cramps, and lightheadedness approximately 2 hours after being injected intraperitoneally into the stomach with 1 mg digoxin. An ECG revealed sinus tachycardia, with a heart rate of 140. An initial digoxin level, obtained 2 hours post-injection, was 8.1 mg/dL and her potassium level was 3.4 mEq/L. Digibind was not administered and, 7 hours post-injection, her digoxin level decreased to 2.5 mg/dL. Following continued observation and resolution of symptoms, she was discharged 24 hours later. The outcome of the fetus was unknown (Mellesmoen & Gummin, 2015).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) GENERAL

a) Digoxin toxicity has been reported in 4 patients with normal therapeutic serum digoxin levels (0.6-2.6 ng/mL). Gastrointestinal symptoms of major bowel disease was evident in 3 of the patients and tiredness and bradycardia was reported in 1 patient (Mitchell, 1997).

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) ADULT

a) Following an overdose of digitoxin, one patient died from ventricular fibrillation 24 hours after admission, with a plasma digitoxin concentration of 124 nanograms/milliliter (160 millimoles/liter) shortly before death (Hansteen et al, 1981).
b) A serum digoxin concentration of 38.5 nanomoles/liter at 4 hours and 40 minutes following an overdose of 100 digoxin tablets 0.1 milligram (total of 10 milligrams) and increasing to a peak of 93.6 nanomoles/liter at 24 hours was reported in a 79-year-old male, who died 12 days later of septic shock (Behringer et al, 1998).
c) An 82-year-old male with underlying heart disease (treated with digoxin during the previous 2 years) ingested a full bottle of digoxin (quantity and strength not reported). He developed fatal cardiac arrest 4 hours later. A serum sample taken 2.5 hours after the ingestion, revealed a serum digoxin concentration between 12.2 and 13.2 nanograms/milliliter (Rodriguez-Calvo et al, 2002).
d) CASE SERIES - In a case series of 1,433 patients with digoxin assays, 115 (8%) were reported to have elevated levels (greater than 2.4 ng/mL). Eighty- two of these had complete records, and 59 (72%) of these had experienced electrocardiographic or clinical features of digoxin toxicity. A combination of impaired renal function, particularly in elder patients, and drug interactions mainly contributed to the elevated digoxin serum levels (Marik & Fromm, 1998).
e) Retrospective analysis of data from the DIG trial indicates a beneficial effect of digoxin on morbidity and no excess mortality in women at serum concentrations from 0.5 to 0.9 ng/mL, whereas serum concentrations greater or equal to 1.2 ng/mL may be harmful (Adams et al, 2005).

2) PEDIATRIC

a) CASE REPORT - Two weeks after undergoing an open-heart surgery, a 12-week-old girl with known cardiac disease (a double outlet right ventricle with a subaortic ventricular septal defect and a single coronary artery) presented in asystolic cardiac arrest secondary to an acute on chronic digoxin poisoning (125 mcg twice daily instead of 25 mcg twice daily; 750 mcg over a 3-day period instead of 150 mcg). Her digoxin level was 12.6 ng/mL. Following a successful resuscitation and the use of Digoxin-specific antibody fragments, she converted to normal sinus rhythm. She was discharged 6 days after the admission with full neurological recovery (Eyal et al, 2005).

Workplace Standards

1) Not Listed

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

1) Not Listed

Toxicity Information

7.7.1)

A) DIGITOXIN

1) LD50- (ORAL)MOUSE:

a) 5 mg/kg (RTECS , 2001)

2) LD50- (ORAL)RAT:

a) 24 mg/kg (RTECS , 2001)

B) DIGOXIN

1) LD50- (ORAL)MOUSE:

a) 18 mg/kg (RTECS , 2001)

2) LD50- (ORAL)RAT:

a) 28 mg/kg (RTECS , 2001)

C) OUABAIN

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 11 mg/kg ((RTECS, 1998))

2) LD50- (ORAL)MOUSE:

a) 5 mg/kg ((RTECS, 1998))

3) LD50- (SUBCUTANEOUS)MOUSE:

a) 5 mg/kg ((RTECS, 1998))

Pharmacology Toxicology

Toxicologic Mechanism

Physicochemical

Physical Characteristics

1) Odorless (HSDB, 2003)
2) Clear to white crystals or a white, crystalline powder (HSDB, 2003)
3) Radially arranged, four- and five-sided triclinic plates from dilute alcohol or dilute pyridine (Budavari, 1996)

1) White or pale buff microcrystalline powder or elongated leaflets(HSDB, 2003)
2) Very small elongated, rectangular plates from dilute alcohol (Budavari, 1996)

1) Odorless, white, hygroscopic, crystalline powder as an octahydrate (HSDB, 2003)
2) Stable in air but is affected by light (Budavari, 1996)

Molecular Weight

Animal Toxicology

References

General Bibliography

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CARDIAC GLYCOSIDES

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Treatment Overview

Range Of Toxicity

Life Support

Clinical Effects

Laboratory Monitoring

Summary Of Exposure

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hematologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

General Bibliography