1. Digoxin Toxicity Allison A. Muller, PharmD, D.ABAT
Dr. Muller reports a financial relationship with BTG International, Inc. as a consultant.  This slide presentation was produced as part of this relationship. She reports no other conflicts. The supervising editor was Richard C. Dart, MD, PhD.

2. Cardioactive Steroids also known as cardiac glycosides1

3. Cardioactive Steroids
Cardioactive Steroids (CAS), or cardiac glycosides, developed their name from the strong cardiac effect on the heart and the recognition of a common steroid nucleus at the heart of these drugs.
The most common pharmaceutical product is digoxin. Other preparations available internationally include digitoxin, ouabain, lanatoside C, deslanoside, and gitaline.
There is evidence in the Ebers Papyrus (Papyrus Smith) that the Egyptians used plants containing CAS at least 3000 years ago. 2

4. Cardioactive Steroids: Sources
Many plants contain cardioactive steroids
Digitalis purpurea (foxglove), Nerium oleander (oleander), Convallaria majalis (lily of the valley), Drimia maritima (red squill)
Toxicity may result from use of herbal products or teas derived from such plants or direct ingestion of the plant itself
Bufo marinus toad – dried secretions are a supposed aphrodisiac and contain a cardioactive steroid
Giardina EG, Sylvia L. Up to Date, Rose BD (ED), Waltham, MA, 2012. 3

5. Cardioactive Steroids: Effect
At therapeutic serum concentrations, CAS increase automaticity and shorten the repolarization intervals of the atria and ventricles.
Changes in nodal conduction cause a decrease in ventricular response rate to suprajunctional rhythms and by PR interval prolongation (digitalis effect). 4

6. Injection (IV; rarely used IM)
Digoxin: Mechanism
Formulations
Injection (IV; rarely used IM)
Oral Solution
Tablets
Mechanism of Action
Inhibit active transport of Na+ and K+ across the cell membrane during repolarization by binding to a specific site on the extracellular face of the alpha-subunit of the membrane Na+-K+-ATPase
Digoxin
Ca++ K+ K+ K+ K+
Na+ K+ K+
Ca++
Na+
Ca++ K+
Na+
Ca++
By blocking the receptor, digoxin increases the amount of K+ and Ca2+ in the cell, while increasing the level of Na+ outside of the cell.
Na+ K+
Na+
Na+ K+
Na+
Na+
Ca++ K+
Na+
Ca++
Na+
Na+
Na+
Arispe N, Diaz JC, Simakova O, Pollard HB. Heart failure drug digoxin induces calcium uptake into cells by forming transmembrane calcium channels. Proc Natl Acad Sci. 2008;105:
Middlekauff HR. Int Med 1998; 37: 5

7. Digoxin: Therapeutic Role
Disease states used in:
Atrial fibrillation:
Control of ventricular response rate in patients with chronic atrial fibrillation
Heart failure:
Increases left ventricular ejection fraction by increasing exercise capacity, and decreasing heart failure-related hospitalizations and emergency room visits. Likely no effect on mortality
Used in adults and pediatrics
FDA Package Insert for Digoxin, accessed 11/13/2013 6

8. Volume of Distribution
Digoxin: Kinetics
Volume of Distribution
Protein Binding
Half Life
Time to peak (serum)
5-7 L/kg
25%
Age, Renal, and cardiac function dependent
Approximately Hours (parent drug)
Oral: 1-3 hours
Distribution phase: 6-8 hours
Steady state: Days
FDA Package Insert for Digoxin, accessed 11/13/2013 7

9. Digoxin: Times to Onset of Pharmacologic Effect and to Peak Effect of Preparations
Tablets
IV/Injection
Time to onset of Effect: Hours
Time to Peak Effect: Hours
Time to onset of Effect: Minutes
Time to Peak Effect: Hours 8

10. Digoxin Toxicity
Overall use of digoxin has declined approximately 10% in hospitalized acute decompensated heart failure patients.
(from 31.4% in 2001 to 23.5% in 2004)
Number of patients with admitted digoxin poisoning has remained stable (approximately 1,500/year)
Use of digoxin-specific antibody fragments has increased (approximately 20%)
2513 cases and 1601 of these were single exposure cases (that is, no co-ingestants)
In 2011, there were 2,513 cases involving cardiac glycosides reported to U.S. poison control centers. Of these, 90 experienced major effects (i.e, life threatening resulting in prolonged hospitalization) and 26 died.
Hussain Z, Swindle J, Hauptman PJ. J Card Fail 2006; 12: 343.
Bronstein AC, Spyker DA, Cantilena LR, et al. Clin Tox 2012; 50: 9

11. Risk Factors for Digoxin Toxicity
Kidney Injury: digoxin is primarily eliminated by the kidneys
Age: elderly are more likely to have decreased renal function and taking potentially interacting concomitant medications
Electrolyte Imbalance: increases sensitivity to digoxin effects
Fluid Status: fluid loss or poor fluid intake can lead to electrolyte imbalances
FDA Package Insert for Digoxin, accessed 11/13/2013 10

12. Digoxin: Causes of Toxicity
Hypokalemia
Hypercalcemia
Hypomagnesemia
Results in increased digoxin binding increasing its therapeutic and toxic effects.
Digoxin enhances Ca+2 absorption into cardiac myocytes, which is one of the ways it increases inotrophy. This can also lead to Ca+2 overload and increased susceptibility to digitalis-induced arrhythmias.
Can sensitize the heart to digitalis-induced arrhythmias (includes any arrhythmia except supraventricular tachydysrhythmias).
FDA Package Insert for Digoxin, accessed 11/13/2013 11

13. Digoxin: Causes of Toxicity
Drug interactions: many commonly used drugs interact with digoxin
No P450 Interactions
Drugs that alter renal clearance can affect digoxin concentration
Gomes T , Mamdani MM, Juurlink DN. Clin Pharm & Therap 2009; 86:
FDA Package Insert for Digoxin, accessed 11/13/2013 12

14. Digoxin: Causes of Toxicity
Drug interactions: many commonly used drugs interact with digoxin
Loop and Thiazide Diuretics decrease serum potassium levels:
furosemide
hydrochlorthiazide
Gomes T , Mamdani MM, Juurlink DN. Clin Pharm & Therap 2009; 86: 13

15. Digoxin: Causes of Toxicity
Drug interactions: many commonly used drugs interact with digoxin
Various drugs alter the mechanism of digoxin renal excretion or intestinal p-glycoprotein activity
verapamil
diltiazem
quinidine
amiodarone
Gomes T , Mamdani MM, Juurlink DN. Clin Pharm & Therap 2009; 86: 14
FDA Package Insert for Digoxin, accessed 11/13/2013

16. Digoxin: Causes of Toxicity
Increased Serum Levels
Amiodarone
Indomethacin
Quinidine
Benzodiazepines
Itraconazole
Quinine
Bepridil
Macrolide Antibiotics
Spironolactone
Cyclosporine
Propafenone
Tetracyclines
Diphenoxylate
Propantheline
Verapamil
Decreased Serum Levels
Oral aminglycosides
Metoclopramide
Al+/Mg+ containing antacids
Neomycin
Antineoplastics
Penicillamine
Activated charcoal
Rifampin
Cholestyramine
St. John’s wort
Colestipol
Sulfasalazine
Kaoline / pectin .
Gomes T , Mamdani MM, Juurlink DN. Clin Pharm & Therap 2009; 86: 15

17. Digoxin: Causes of Toxicity, Con’t
Enhanced Pharmacodynamic Effects
Beta-blockers
Succinylcholine
Calcium
Sympathomimetics
Verapamil
Diuretics
Diltiazem
Antagonize Pharmacodynamic Effects
Thyroid hormones
Gomes T , Mamdani MM, Juurlink DN. Clin Pharm & Therap 2009; 86: 16

18. Digoxin: Toxicity Signs/symptoms of acute toxicity Gastrointestinal
Neurological
nausea, vomiting, abdominal pain
weakness, confusion
Electrolyte
Cardiac
Hyperkalemia (> 5.5 mEq/L is a poor prognostic sign)
bradycardia, heart block, several types of arrhythmias
Schaeffer TH, Mlynarchek SL, Stanford CF. JAOA 2010; 110: 17

19. Digoxin: Toxicity Signs/symptoms of chronic toxicity Gastrointestinal
Neurological
Patients may have more subtle signs of acute digoxin toxicity (nausea, anorexia)
confusion, drowsiness, headache, hallucinations
Visual
sensitivity to light, yellow halos around lights, blurred vision
Schaeffer TH, Mlynarchek SL, Stanford CF. JAOA 2010; 110: 18

20. Digoxin: Laboratory Analyses
Interpreting laboratory values in the digoxin poisoned patient
Hyperkalemia: > 5.5 mEq/L in the acutely poisoned digoxin patient (100% Mortality)
Poor prognostic sign in acute toxicity. Antidote warranted when > 5 mEq/L due to 50% mortality for potassium 5 mEq/L – 5.5 mEq/L
Hypokalemia: Can predispose the patient to further dysrhythmias and should be corrected with close monitoring to avoid hyperkalemia. Goal Potassium level 4.0 mEq/L mEq/L 19

21. Digoxin: Laboratory Analyses
Interpreting laboratory values in the digoxin poisoned patient
Hypomagnesemia may cause refractory hypokalemia
Administration of magnesium is contraindicated in:
Bradycardia
Heart block
Pre-existing hypermagnesemia
Decreased renal function or failure 20

22. Digoxin: Laboratory Analyses
Digoxin levels in the poisoned patient
Obtaining an immediate digoxin level in an acutely poisoned patient will not reflect the peak serum level as the distribution phase of digoxin is long. An initial 4-6 hour post-ingestion level is appropriate.
Useful following administration of digoxin-specific Fab fragments
Unbound digoxin
Serum concentrations predict cardiac concentrations
Fab fragments of digoxin-specific antibodies will cause a rise in total digoxin levels (as Fab bound digoxin is also being measured)
Total digoxin
(bound & unbound) 21

23. Diagnosis of Digoxin Toxicity
What is needed?
History
Signs and symptoms
EKG
Digoxin levels
Electrolytes 22

24. Diagnosis of Digoxin Toxicity
What is needed?
History
Risk factors for digoxin toxicity including age of patient (for patients chronically using digoxin therapeutically)
Initiation or discontinuation of drugs that potentially interact with digoxin
Any disease changes (such as thyroid disease)
Altered renal function 23

25. Diagnosis of Digoxin Toxicity
What is needed?
Signs and Symptoms
Acute overdose:
Gastrointestinal: nausea, vomiting
Central Nervous System:
confusion, weakness, lethargy
Electrolyte changes: hyperkalemia
Cardiac Signs: sinus bradycardia, second or third degree AV block. Any type of dysrhythmia is possible 24

26. Diagnosis of Digoxin Toxicity
What is needed?
Signs and Symptoms
Chronic overdose (symptoms usually insidious in onset):
Gastrointestinal:
anorexia, nausea,
vomiting, weight loss
Central Nervous System: delirium, hallucinations, confusion,, lethargy (seizures are possible but rare)
Visual: photophobia, changes in color vision (such as yellow halos around lights)
Electrolyte changes: hyperkalemia (sometimes hypokalemia especially if diuretics are used)
Cardiac Signs: bradydysrhythmias (often unresponsive to atropine) ventricular tachydysrhythmias 25

27. Diagnosis of Digoxin Toxicity
What is needed?
EKG
Almost any arrhythmia or conduction abnormality may be seen with digitalis toxicity.
Abnormal rhythms due to digitalis toxicity include the following:   •  Ventricular premature beats   •  Atrial tachycardia (automatic, accelerated, or non-paroxysmal)   •  Atrioventricular junctional tachycardia (automatic or non-paroxysmal)   •  Accelerated junctional rhythm (automatic or non-paroxysmal)   •  Accelerated ventricular rhythm (automatic or non-paroxysmal)   •  Ventricular tachycardia   •  Bidirectional tachycardia (usually  a junctional tachycardia with alternating right and left bundle branch block)   •  Ventricular fibrillation Abnormal conduction due to digitalis toxicity includes the following:   •  Sinus bradycardia   •  Sinus pause or arrest   •  Sinoatrial block   •  First degree atrioventricular block   •  Second degree atrioventricular block (Mobitz 1 or Mobitz 2)   •  Third degree atrioventricular block Combined arrhythmia and conduction abnormalities due to digitalis toxicity include the following:   •  Atrial tachycardia with atrioventricular junctional block (PAT with block) (show ECG 9)   •  Sinus bradycardia associated with atrioventricular junctional tachycardia   •  Accelerated junctional rhythm associated with underlying atrial fibrillation (atrial fibrillation with regularization) Thus, almost any arrhythmia or conduction abnormality may be seen with digitalis toxicity. Atrial flutter, atrial fibrillation, and Mobitz type II second degree AV block are the least likely of all the possible abnormalities 26

28. Diagnosis of Digoxin Toxicity
What is needed?
Digoxin levels
Therapeutic range of digoxin has historically been ng/mL.
Current FDA Package Insert recommends ng/mL.
Toxicity begins >2.0 ng/mL
However, this can be misleading in the acutely poisoned patient
Stat levels may not correlate with the severity of the poisoning especially in acute ingestions
Digoxin’s long distribution phase results in high serum levels for hours prior to completed tissue distribution
Abnormal rhythms due to digitalis toxicity include the following:   •  Ventricular premature beats   •  Atrial tachycardia (automatic, accelerated, or non-paroxysmal)   •  Atrioventricular junctional tachycardia (automatic or non-paroxysmal)   •  Accelerated junctional rhythm (automatic or non-paroxysmal)   •  Accelerated ventricular rhythm (automatic or non-paroxysmal)   •  Ventricular tachycardia   •  Bidirectional tachycardia (usually  a junctional tachycardia with alternating right and left bundle branch block)   •  Ventricular fibrillation Abnormal conduction due to digitalis toxicity includes the following:   •  Sinus bradycardia   •  Sinus pause or arrest   •  Sinoatrial block   •  First degree atrioventricular block   •  Second degree atrioventricular block (Mobitz 1 or Mobitz 2)   •  Third degree atrioventricular block Combined arrhythmia and conduction abnormalities due to digitalis toxicity include the following:   •  Atrial tachycardia with atrioventricular junctional block (PAT with block) (show ECG 9)   •  Sinus bradycardia associated with atrioventricular junctional tachycardia   •  Accelerated junctional rhythm associated with underlying atrial fibrillation (atrial fibrillation with regularization) Thus, almost any arrhythmia or conduction abnormality may be seen with digitalis toxicity. Atrial flutter, atrial fibrillation, and Mobitz type II second degree AV block are the least likely of all the possible abnormalities 27

29. Diagnosis of Digoxin Toxicity
What is needed?
Electrolytes
Hypokalemia results in increased digoxin binding increasing its therapeutic and toxic effects.
Hypercalcemia enhances digitalis-induced inotropy leading to possible Ca+2 overload and increased susceptibility to digitalis-induced arrhythmias.
Hypomagnesemia can sensitize the heart to digitalis-induced arrhythmias.
Abnormal rhythms due to digitalis toxicity include the following:   •  Ventricular premature beats   •  Atrial tachycardia (automatic, accelerated, or non-paroxysmal)   •  Atrioventricular junctional tachycardia (automatic or non-paroxysmal)   •  Accelerated junctional rhythm (automatic or non-paroxysmal)   •  Accelerated ventricular rhythm (automatic or non-paroxysmal)   •  Ventricular tachycardia   •  Bidirectional tachycardia (usually  a junctional tachycardia with alternating right and left bundle branch block)   •  Ventricular fibrillation Abnormal conduction due to digitalis toxicity includes the following:   •  Sinus bradycardia   •  Sinus pause or arrest   •  Sinoatrial block   •  First degree atrioventricular block   •  Second degree atrioventricular block (Mobitz 1 or Mobitz 2)   •  Third degree atrioventricular block Combined arrhythmia and conduction abnormalities due to digitalis toxicity include the following:   •  Atrial tachycardia with atrioventricular junctional block (PAT with block) (show ECG 9)   •  Sinus bradycardia associated with atrioventricular junctional tachycardia   •  Accelerated junctional rhythm associated with underlying atrial fibrillation (atrial fibrillation with regularization) Thus, almost any arrhythmia or conduction abnormality may be seen with digitalis toxicity. Atrial flutter, atrial fibrillation, and Mobitz type II second degree AV block are the least likely of all the possible abnormalities 28

30. Digoxin Toxicity: Available Treatments
Decontamination/enhanced elimination
For acute overdose: Activated charcoal can adsorb digoxin in the gut
Enhanced elimination (dialysis, hemoperfusion) does not effectively remove digoxin due to large volume of distribution and relatively high protein binding 29

31. Digoxin Toxicity: Available Treatments
Fab fragments of digoxin-specific antibodies
Available U.S. products:
DigiFab® digoxin immune fab (ovine) BTG International, Inc. 30

32. Digoxin immune fab (ovine): Indications
Life-threatening or potentially life-threatening digoxin toxicity or overdose, which includes:
Known suicidal or accidental Ingestion of fatal digoxin doses:
10 mg or more in healthy adults
4 mg (0.1 mg/kg) or more in healthy children
An amount that results in steady state digoxin
concentrations of > 10 ng/mL
Chronic ingestions:
Serum digoxin > 6 ng/mL in adults or 4 ng/mL in children
DigiFab® Prescribing Information, Jan 2012, BTG International, Inc. 31

33. Digoxin immune fab (ovine): Indications
Life-threatening or potentially life-threatening digoxin toxicity or overdose, which includes:
Severe ventricular arrhythmias
Progressive bradycardia
Second or third degree heart block unresponsive to atropine
Serum potassium levels > 5.5 mEq/L (adults) or 6 mEq/L (children) with rapidly progressive signs and symptoms of digoxin toxicity
DigiFab® Prescribing Information, Jan 2012, BTG International, Inc. 32

34. Digoxin immune fab (ovine): Mechanism of Action
Binds to digoxin molecules, reducing free digoxin levels
Results in a shift in the equilibrium away from receptor binding
Fab-digoxin complexes are cleared by the kidney and mononuclear phagocyte system
DigiFab® Prescribing Information, Jan 2012, BTG International, Inc. 33

35. Digoxin immune fab (ovine): Dosing
Acute ingestion: unknown amounts of digoxin and unknown serum concentration
20 vials of Digoxin immune fab (ovine)
Monitor for volume overload in children < 20 kg
Can split dose into 10 vials followed by another 10 vials to avoid a febrile reaction
DigiFab® Prescribing Information, ,an 2012, BTG International, Inc. 34

36. Digoxin immune fab (ovine): Dosing
Acute ingestion: known amounts of digoxin
Amount of digoxin ingested (mg)*
Dose In Vials =
0.5 mg/Vial
Each vial of DigiFab®(40 mg of digoxin-specific Fab) binds approx. 0.5 mg of digoxin
* multiply mg by bioavailability of the tablet formulation:
0.25 mg tabs (80% bioavailability)
0.2 mg tabs (100% bioavailability)
DigiFab® Prescribing Information, Jan 2012, BTG International, Inc. 35

37. Digoxin immune fab (ovine): Dosing
Chronic ingestion: unknown serum digoxin concentration
6 Vials of Digoxin immune fab (ovine) in Adults and Children > 20 Kg
1 Vial of Digoxin immune fab (ovine) in Infants and Children < 20 Kg
DigiFab® Prescribing Information, Jan 2012, BTG International, Inc. 36

38. Digoxin immune fab (ovine): Dosing
Chronic ingestion: known digoxin serum concentration
(Serum Digoxin ng/mL) x (Weight in kg)
Dose In Vials =
100
DigiFab® Prescribing Information, Jan 2012, BTG International, Inc. 37

39. Digoxin immune fab (ovine): Preparation
Reconstitution: add 4 mL Sterile Water for Injection (10 mg/mL solution of digoxin immune fab protein) and gently mix
Use immediately or store in refrigerator for up to 4 hours (do not freeze)
One vial contains 40 mg of digoxin immune fab protein
Contains no preservatives and is for one-time use only
DigiFab® Prescribing Information, Jan 2012, BTG International, Inc. 38

40. Digoxin immune fab (ovine): Preparation
Add reconstituted product to appropriate 0.9% sodium chloride for injection
For infants and very small children
use undiluted reconstituted solution using tuberculin syringe
reconstituted vial can also be diluted with an additional 36 mL of isotonic saline for 1mg/mL concentration
Visual inspection
Do not use if solution is cloudy, turbid or contains particulates
DigiFab® Prescribing Information, Jan 2012, BTG International, Inc. 39

41. Digoxin immune fab (ovine): Administration
30 minute slow IV infusion
Can be given by IV bolus injection if cardiac arrest is imminent
DigiFab® Prescribing Information, Jan 2012, BTG International, Inc. 40

42. Digoxin immune fab (ovine): Dosing/administration
If toxicity is not adequately reversed or recurs, measure free (not total) serum digoxin concentrations
Repeat doses may be guided by clinical judgment
If digoxin toxicity is not at all reversed, consider another diagnosis
DigiFab® Prescribing Information, Jan 2012, BTG International, Inc. 41

43. Digoxin immune fab (ovine): Use in Special Populations
Pregnancy category C
Nursing mothers
Unknown if may cause fetal harm. Should be given to pregnant patient only if clinically indicated
Unknown if excreted in breast milk
Pediatric use
Geriatric patients
Pediatric safety data are limited. Pediatric dosing estimations are based on adult dosing
Renal function needs to be monitored closely for recurrent toxicity
DigiFab® Prescribing Information, Jan 2012, BTG International, Inc. 42

44. Digoxin immune fab (ovine): Warnings
Monitor potassium level frequently as a rapid drop in serum potassium may occur following digoxin immune fab (ovine): administration
DigiFab® Prescribing Information, ,Jan 2012, BTG International, Inc. 43

45. Digoxin immune fab (ovine): Warnings
Patients who require digoxin’s inotropic action may deteriorate secondary to the withdrawal of digoxin’s inotropic action by digoxin immune fab (ovine)
Additional inotropic support may be required for these patients (e.g, dopamine, dobutamine or vasodilators)
Re-digitalization may need to be postponed until digoxin immune fab (ovine) has cleared (several days to more than a week of impaired renal function)
DigiFab® Prescribing Information, Jan 2012, BTG International, Inc. 44

46. Digoxin immune fab (ovine): Warnings
Do not administer digoxin immune fab (ovine) to papaya-or papain-hypersensitive patients unless the benefits clearly outweigh the risks
Patients with allergies to sheep protein or prior treatment with ovine antibodies or Fab are at risk for an anaphylactic reaction
Standard emergency care and termination of digoxin immune fab (ovine) are warranted for patients with anaphylaxis/ hypersensitivity reactions
DigiFab® Prescribing Information, Jan 2012, BTG International, Inc. 45

47. Digoxin immune fab (ovine): Adverse effects (most common)
Worsening of congestive heart failure 13%
Hypokalemia %
A rapid shift of potassium back into the cell can occur when digoxin toxicity is reversed by digoxin immune fab (ovine)
Serum potassium should be followed closely and supplementation should be given cautiously
Worsening atrial fibrillation %
DigiFab® Prescribing Information, Jan 2012, BTG International, Inc. 46

48. Digoxin immune fab (ovine):
Minimum stocking recommendation: 15 vials (for approximately 8 hours of initial therapy)
Emergency department stocking: for availability within one hour
Dart RC, Borron SW, Caravati EM, et al. Ann Emer Med 2009; 54: 47

49. Resources Website for product information US Poison Centers
(calls routed to appropriate center)
BTG Medical Info/Adverse Event Reporting
Customer Service including availability 48

50. Digoxin Toxicity: Case 1
76 year old woman with history of atrial fibrillation, hypertension, renal impairment, breast cancer, osteoarthritis. Stroke 1 month prior to admission.
Medications: digoxin 250 mcg once daily, amlodipine, lisinopril, indapamide SR, simvastatin, clopidogrel, bisoprolol, omeprazole, erythromycin
Presents with nausea, vomiting, change in vision, lethargy
VS: BP “normal”; HR bpm
Labs
Digoxin levels: prior to admission: 3.4 ng/mL (0.8-2 ng/mL normal range for this lab)
On admission: 2.9 ng/mL
Increased digoxin dose from 125 mcg/day to 250 mcg/day 28 days ago
Kolev KK. Digoxin – a friend or foe. BMJ Case Reports 2012 Sept 24 49

51. Digoxin Toxicity: Case 1
Summary: elderly patient with renal impairment, signs/symptoms of (chronic) digoxin poisoning with elevated digoxin level
Potential drug interactions:
Amlodipine
Bisoprolol
Erythromycin
(Ca+2 channel blocker) can increase digoxin level and enhance digoxin AV blocking effect
(ß blocker) can enhance digoxin’s bradycardic effect
(macrolide antibiotic) can increase digoxin level
Kolev KK. Digoxin – a friend or foe. BMJ Case Reports 2012 Sept 24 Gomes T, Mamdani MM, Juurlink DN. Clin Pharmacol & Therap 2009; 86: 50

52. Digoxin Toxicity: Case 1
Received digoxin-specific antibody fragments (Fab)
Weight 108 kg
Digoxin level: 2.9 ng/mL
(Serum Digoxin ng/mL) x (Weight in kg)
Fab Dose In Vials =
100
3 vials administered
Kolev KK. Digoxin – a friend or foe. BMJ Case Reports 2012 Sept 24 51

53. Digoxin Toxicity: Case 1
6 hours post digoxin Fab infusion: digoxin 1.9 ng/mL
At discharge (91 hours post digoxin Fab infusion): digoxin ng/mL, HR 65 bpm, digoxin toxicity signs/symptoms resolved
Monitoring
HR: improved (35-38 bpm to 65 bpm at discharge)
BP: remained stable
EKG: unchanged from baseline (atrial fibrillation)
K+ not provided in this report (although this was a chronic toxicity not acute)
Kolev KK. Digoxin – a friend or foe. BMJ Case Reports 2012 Sept 24 52

54. Digoxin Toxicity: Case 1
Approaches to digoxin poisoning in the chronically poisoned patient will depend on the status of the patient (signs/symptoms, age, renal function, cardiac status)
This was an elderly patient with impaired renal function who clearly had digoxin toxicity and an elevated level.
The clinical decision was made to treat promptly with digoxin Fab rather than prolong her clinical course.
Kolev KK. Digoxin – a friend or foe. BMJ Case Reports 2012 Sept 24 53

55. (includes off-label information)
Supplemental slides
(includes off-label information) 54

56. Treating non-pharmaceutical sources of cardioactive steroids
Natural cardioactive steroid sources:
Yellow oleander
Oleander
Squill
Lily of the valley
Bufos marinus toad
DigiFab® is not FDA-approved for treating poisoning from these naturally occurring steroids; however, there is evidence in the literature for its use.
Howland MA. Antidotes in Depth: Digoxin-Specific Antibody Fragments. Goldfrank’s Toxicologic Emergencies, 8th edition
Brubacher J. Toxicon 1999; 37:
Cheung K. J Pediatr Child Health 1991; 27:
Eddleston M. Lancet 2000; 355:
Flanagan RJ. Drug Saf 2004; 27: 55

57. Digoxin Toxicity: Calcium Use
Historically calcium has been contraindicated in digoxin-poisoned patients (often considered if patient also is poisoned by calcium channel blocker or is hyperkalemic)
Intracellular hypercalcemia is already present and additional calcium theoretically may result in synergistic cardiac effects with digoxin and result in hypercontractility or hypocontractility (“stone heart”) and cardiac arrest
However, a recent study did not support this theory.
Since cardioactive steroid toxicity causes intracellular myocardial hypercalcemia, giving exogenous calcium may worsen conduction abnormalities and result in cardiac arrest.
Levine M, Nikkanen H, Pallin DJ. J of Emerg Med 2011; 40: 56