I. How to Use
When to Use
The DigiFab® Dosing calculator can be useful for acute, acute on chronic, or chronic digoxin toxicity, or in those with poisoning with cardioactive steroids, such as plants like foxglove and lily of the valley.
Pearls / Pitfalls
There are many things to consider before using DigiFab®. First, cardioactive steroid toxicity can cause nearly any dysrhythmia except for rapidly conducted supraventricular tachydysrhythmia. Second, the serum digoxin level must be obtained at steady-state (i.e., obtained ≥6 hours after ingestion). The serum digoxin level may be misleadingly high if obtained <6 hours after ingestion. Third, hyperkalemia acts as a marker of poisoning severity in acute digoxin overdose. Correcting mild elevations in serum potassium without administering DigiFab® will not improve survival (see Next Steps for details). Fourth, impaired creatinine clearance and aging (associated with decreased function of renal, hepatic, and cardiac systems) may result in clinical toxicity at lower serum digoxin levels. Fifth, electrolyte abnormalities (specifically hypokalemia and hypomagnesemia) may result in dysrhythmias at lower serum digoxin levels. Lastly, drugs including quinidine, verapamil, diltiazem, carvedilol, amiodarone, and spironolactone will result in decreased digoxin protein binding, thereby increasing free digoxin levels. Notably, patients with pacemakers may not display classic electrocardiogram (ECG) findings and have a paced rhythm without ventricular ectopy despite presence of moderate to severe digoxin toxicity. Consider treatment if hemodynamic instability, serum potassium > 5.5 mEq/L or significant clinical symptoms of digoxin toxicity. The clinical symptoms of digoxin toxicity fall into three main categories: gastrointestinal, visual/neurologic, and cardiac. Gastrointestinal symptoms are often the earliest signs of digoxin toxicity and include nausea, vomiting, abdominal discomfort, and loss of appetite. Visual and neurological symptoms include yellow or green vision, or seeing ‘halos’ around lights, blurry vision, and other neurological symptoms include confusion, dizziness, delirium, headache. The cardiac manifestations include bradycardia and arrhythmias such as premature ventricular contractions (PVCs), atrial tachycardia with block, junctional rhythms, other AV blocks (first, second or third) and/or ventricular tachycardia or fibrillation, which can be life threatening. These symptoms are similar in adults and children, with the distinction that in children, the gastrointestinal symptoms may be harder to recognize, and may be seen as irritability or inconsolable crying, with poor feeding or failure to thrive. Visual disturbances are also not reported as commonly in young children. Digoxin levels measured after administration of DigiFab® will be falsely elevated. If required, free digoxin levels will need to be measured (not readily available at all labs).
Why Use
DigiFab® is an effective antidote for acute, acute on chronic, and chronic digoxin toxicity. It is also indicated for poisoning from other cardioactive steroids.
II. Next Steps
Advice
Therapeutic range for serum digoxin level is 0.5–2.0 ng/mL (0.6–2.6 nmol/L). If acute poisoning and serum digoxin concentration is confirmed >10 ng/mL (13nmol/L), give empiric dose (10-20 vials) or if digoxin dose ingested is > 10mg with signs of hemodynamically unstable dysrhythmia (ventricular tachycardia; ventricular fibrillation; asystole; complete heart block, symptomatic bradycardia).
Management
The DigiFab® calculator is appropriate for vials containing (approximately) 40 mg of antibodies which will bind ~0.5mg of digoxin. Slow infusion (i.e., 30 minutes) improves Fab efficacy. This way of infusion is preferable when rhythm disturbances are not life-threatening. In the case of chronic overdose, if digoxin level (in prehospital setting for example) is missing, a dose of 3 vials is appropriate (experience-based recommendation).
Critical Actions
Hypokalemia and hypomagnesemia may worsen digoxin toxicity, even at therapeutic digoxin levels. If mild hyperkalemia, correction is not advised, as treatment with DigiFab® will correct hyperkalemia in setting of acute digoxin toxicity. If DigiFab® is not available, avoid calcium for treatment of hyperkalemia, and avoid beta-2 agonists for concerns for cardiac sensitization. Alongside DigiFab® as first-choice treatment, ventricular arrhythmias can be treated with lidocaine or magnesium sulfate, and bradyarrhythmias with atropine. Replete potassium in the setting of hypokalemia, however do not delay administration of DigiFab® as needed. Though debated, calcium salts should be avoided in patients with hyperkalemia secondary to digoxin toxicity for concern for stone heart and asystole. Transcutaneous and especially transvenous pacing should be avoided in patients with digoxin toxicity due to risk for precipitating dysrhythmias. Extracorporeal removal is not beneficial due to digoxin’s large volume of distribution and molecular weight.
III. Evidence
Evidence Appraisal
The majority of digoxin toxicity cases involve chronic digoxin toxicity. The prescribing information for DigiFab®, the only digoxin immune fab currently marketed in the U.S., recommends empiric fab in cases of known suicidal or accidental consumption of “fatal” doses of digoxin. For both life-threatening and non−life-threatening presentations of toxicity, management options are limited and, with the exception of the administration of digoxin immune Fab, are associated with uncertain efficacy. Further, the threshold and indications for digoxin immune Fab treatment remain clinically uncertain, in part due to cost considerations, lack of data from randomized double-blind, placebo-controlled trials, and relatively modest trends toward decreased mortality. The literature on digoxin toxicity remains limited in quality and scope, with few appropriately powered studies to inform practice and no randomized controlled trials. In a contemporary expert panel, digoxin immune Fab was supported for the following cases: 1) in the setting of life-threatening digoxin exposure to decrease the likelihood of death; 2) in the absence of other clinical findings, treatment when the serum digoxin concentration is >4 ng/mL in patients with acute or chronic digoxin ingestion; 3) in adult patients with acute or chronic digoxin ingestion and suspected digoxin toxicity with no other reason for hyperkalemia, when the serum potassium concentration is ≥6 mEq/L; and 4) in patients with digoxin-associated bradyarrhythmia rather than a temporary transvenous pacemaker.
Formula
Number of vials = ( serum digoxin level, ng/mL x patient weight, kg ) / 100
OR
Number of vials = ( amount ingested, mg / 0.5 mg/vial ) x 80% bioavailability
Number of vials should always be rounded up to the next whole number.
Empiric therapy for acute poisoning:
10-20 vials (adult or child)
Empiric therapy for chronic poisoning:
Adult: 3-6 vials
Child: 1-2 vials
Example: 60-year old woman (65 kg) develops acute kidney injury from gastroenteritis and presents to the ED with altered mental status and bradycardia. Her serum digoxin level is 2.8 ng/mL (3.6 nmol/L). How many vials of DigiFab should be administered?
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No. of vials = ( serum digoxin level, ng/mL x patient weight, kg ) / 100
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No. of vials = 2.8 ng/mL x 65 kg / 100
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No. of vials = 1.82 = 2 vials
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(No. of vials should be rounded up)
Example: a 30-year old man (70 kg) presents to the ED after intentionally ingesting 4 mg of a family member’s digoxin. Atropine IV is ineffective and his heart rate remains 20-30. How many vials of DigiFab should be administered?
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No. of vials = ( amount ingested, mg / 0.5 mg/vial ) x 80% bioavailability
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No. of vials = 4 mg / 0.5 (mg/vial) x 80%
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No. of vials = 6.4 = 7 vials
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(No. of vials should be rounded up)
Facts & Figures
Additional considerations for treatment of digoxin toxicity include: Atropine 0.5 mg IV for adults; 0.02mg/kg IV for children for acute toxicity if bradydysrhythmias or high degree AV block. Cautious correction of electrolyte abnormalities, specifically hypokalemia and hypomagnesemia (may result in dysrhythmias at lower serum digoxin levels). Frequent premature ventricular complexes (PVCs) may be closely followed by ventricular dysrhythmias. Further, digoxin maintenance therapy not be restarted in the acute setting following a presentation with digoxin toxicity that required digoxin immune Fab treatment, except in rare circumstances and after risk-benefit assessment.
Literature
Original/Primary
https://www.ncbi.nlm.nih.gov/pubmed/18824911
Lapostolle F, Borron SW, Verdier C, Taboulet P, Guerrier G, Adnet F, Clemessy JL, Bismuth C, Baud FJ. Digoxin-specific Fab fragments as single first-line therapy in digitalis poisoning. Crit Care Med. 2008 Nov;36(11):3014-8. doi: 10.1097/CCM.0b013e31818b341c.
Validation - validated
URL
Citation in AMA format [?]
Other References (including meta-analyses, CPGs, and impact analyses)
https://www.ncbi.nlm.nih.gov/pubmed/2188752
Antman EM, Wenger TL, Butler VP Jr, Haber E, Smith TW. Treatment of 150 cases of Life-Threatening Digitalis Intoxication With Digoxin-Specific Fab Antibody Fragments: Final Report of a Multicenter Study. Circulation. 1990;81:1744-52.
https://www.ncbi.nlm.nih.gov/pubmed/4715199
Bismuth C, Gaultier M, Conso F, Efthymiou ML. Hyperkalemia in Acute Digitalis Poisoning: Prognostic Significance and Therapeutic Implications. Clin Toxicol. 1973;6(2):153-62.
Digibind® Injection Information, Manufacturer’s Guidelines
https://accesspharmacy.mhmedical.com/book.aspx?bookid=1163
Hack JB. Cardioactive Steroids. In: Hoffman R, Howland MA, Lewin N et al. Goldfrank’s Toxicologic Emergencies, Tenth Edition. McGraw-Hill Education / Medical; 2014.
https://accesspharmacy.mhmedical.com/book.aspx?bookid=1163
Howland MA. Digoxin-Specific Antibody Fragments. In: Hoffman R, Howland MA, Lewin N et al. Goldfrank’s Toxicologic Emergencies, Tenth Edition. McGraw-Hill Education / Medical; 2014.
Andrews P, Anseeuw K, Kotecha D, Lapostolle F, Thanacoody R. Diagnosis and practical management of digoxin toxicity: a narrative review and consensus. Eur J Emerg Med. 2023 Dec 1;30(6):395-401. doi: 10.1097/MEJ.0000000000001065. Epub 2023 Aug 25. PMID: 37650725; PMCID: PMC10599802
Lavonas EJ, Akpunonu PD, Arens AM, Babu KM, Cao D, Hoffman RS, Hoyte CO, Mazer-Amirshahi ME, Stolbach A, St-Onge M, Thompson TM, Wang GS, Hoover AV, Drennan IR; American Heart Association. 2023 American Heart Association Focused Update on the Management of Patients With Cardiac Arrest or Life-Threatening Toxicity Due to Poisoning: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2023 Oct 17;148(16):e149-e184. doi: 10.1161/CIR.0000000000001161. Epub 2023 Sep 18. PMID: 37721023.
Clifford LM, Meere W. Chronic Digoxin Toxicity: An Evaluation of Digoxin-Specific Antibodies and Other Management Options. Cureus. 2023 May 8;15(5):e38692. doi: 10.7759/cureus.38692. PMID: 37292530; PMCID: PMC10245077.