Sir William Withering first described the signs of digoxin toxicity in 1785: ventricular arrhythmias, anorexia, nausea and vomiting, diarrhoea and abdominal discomfort, headache, fatigue, drowsiness, confusion, hallucinations and blurred vision. With the expansion of pharmacokinetic knowledge and therapeutic monitoring of digoxin in clinical practice, and substitution with newer agents, the frequency of digoxin toxicity has decreased. Digoxin toxicity may still occur when heart failure progresses, renal function deteriorates, and medications are misused or undergo interactions.

The presentation of symptoms varies between chronic and acute toxicity. Diagnosis usually isn’t made until electrocardiographic symptoms appear, supported by elevated serum levels of digoxin and electrolytes, and thyroid function assessment. In an acute scenario it is important to ascertain a history, noting the time of administration, as accurate digoxin levels require sampling at least six hours following administration due to the distribution kinetics of the drug.

The target therapeutic range for serum digoxin is 0.6 to 2nmol/L in atrial fibrillation and doses typically range from 125 microgram to 250 microgram daily. In heart failure, the target range is 0.6 to 1nmol/L and doses range from 62.5 microgram to 125 microgram daily. Severe acute toxicity levels are usually in the range of 15nmol/L and can occur after ingestion of approximately 10mg in adults and 4mg in children (40 and 16 tablets of 250 microgram respectively). However, less severe acute toxicity levels could occur with ingestion of much lower doses.

Sudden illness that precipitates dehydration or reduced renal function in patients, such as vomiting or diarrhoea, may result in digoxin toxicity. Serum digoxin concentration does not necessarily correlate to toxicity and must be connected to symptoms prior to treatment. Levels tend to correlate better with symptoms when greater than 2nmol/L, however symptoms may even occur at 1.5nmol/L. To differentiate; acute toxicity symptoms manifest abruptly, usually hours after ingestion, and chronic symptoms tend to be more subtle, occurring over days to weeks. According to the Therapeutic Guidelines, undiagnosed chronic toxicity is associated with a significant risk of fatality within seven days.

The majority of digoxin overdoses can be managed by reduction of absorption with activated charcoal, if intervention occurs within two hours of ingestion. The cardiac symptoms are corrected with atropine and intravenous fluids used to replace volume where contraindications such as heart and kidney failure are absent. Electrolyte disturbances should be addressed with intravenous magnesium or potassium supplementation to correct low concentrations and conversely using insulin with glucose to correct hyperkalaemia.

Digoxin overdose is pharmacologically treated when there is evidence that the overdose is potentially fatal such as the ingestion of a significant dose, cardiac arrest, abnormal serum potassium, ventricular arrhythmias and hypotension from bradycardia. The treatment is an infusion of digoxin antibodies (digoxin-specific immune antigen binding fragments [digoxin immune Fab]) of ovine origin and supportive measures.

Digoxin antibodies strongly bind to molecules of digoxin, making the drug unavailable for activity at myocardial cell sodium/potassium adenosine triphosphatase pump. The antibody digoxin complex accrues in serum and is renally excreted within 12 to 24 hours. If the patient has poor renal function which is associated with heart failure, there may be time for digoxin to dissociate from the antibody complex and allow recurrence of poisoning to occur. Digoxin antibodies efficiently reverse the effects of digoxin toxicity with improvement noticeable within 30 minutes and completion at around four hours after infusion.

Pathology testing of digoxin levels will spike after administration of digoxin antibodies because it measures both bound and unbound drugs in blood serum. Free digoxin may be approaching zero; however digoxin levels may indicate toxic results therefore it is not recommended to rely on plasma digoxin concentration alone. It is recommended to also monitor cardiac symptoms. A vial of digoxin antibodies contains 38mg of digoxin Fab, which will bind approximately 0.5mg of digoxin absorbed. Therefore, in acute toxicity circumstances where the dose ingested is known, an appropriate dose of digoxin antibodies can be administered. For example, where vials = body burden/0.5mg, if a patient consumes 50 digoxin tablets of 250 microgram (total dose = 12.5mg) of which 80% is absorbed from the gastrointestinal tract; the body burden equals 10mg. This would require 20 vials (720mg) of digoxin antibody for treatment.

In acute overdoses where the amount ingested is not known, the Therapeutic Guidelines suggest administering 10 vials (380mg) of digoxin antibodies. This dose is the estimated effective treatment for a 60kg patient with a serum digoxin level of 16nmol/L, or a 100kg patient with a serum digoxin level of 8nmol/L. If there is an unsatisfactory response after 30 to 60 minutes the 380mg dose is repeated. This composite dose would be effective for a 100kg patient with a serum level of 20nmol/L. If there is deterioration after 12 hours of monitoring, the 380mg dose should be repeated. It is important to note that pathology assays may be a source of error as they are not designed to measure values greater than 5nmol/L and therefore empiric dose regimes as described above are appropriate. If the blood serum concentration is known, the dose may be calculated using the same method as used for chronic overdose.

In chronic overdose, serum digoxin tends to be lower than in acute overdose and can usually be managed with supportive measures, withholding digoxin until the patient’s status improves, and then reassessing the dose. According to the digoxin antibody product information, antidote treatment is only indicated when serum digoxin levels reach more than 10nmol/L. As the effect of repeated use of digoxin antibodies is not known, its use is reserved for severe toxic manifestations.

The Therapeutic Guidelines suggest using digoxin antibodies where there are substantial toxicity symptoms associated with levels above 2nmol/L. Using two vials of digoxin antibodies where digoxin levels are unknown may be of benefit. When levels are known, which is often the case in the hospital setting, the body burden should be calculated using the volume of distribution of digoxin (~ 7L/kg), the patient’s weight (e.g. 70kg) and the serum digoxin level (e.g. 10nmol/L).

Body burden = 10nmol/L x 7L/kg x 70kg
= 4,900nmol
= 3.8mg (or ≈ 4mg)
Number of vials = body burden
        0.5mg
= 8 vials (304mg)

Lethal symptoms of overdose may occur in chronic overdoses at levels as low as 2nmol/L. The empirical treatment of such symptoms with two vials repeated every 30 to 60 minutes in these scenarios would be appropriate. If such symptoms are not resolved after the second infusion, clinical toxicology consultation should be arranged.

In summary, digoxin overdose may result in principal symptoms of gastrointestinal upset, visual disturbances, drowsiness, weakness, confusion, delirium, tachypnoea and heart palpitations. After acute ingestion of massive doses, where the amount of digoxin cannot be ascertained, the practical standard dosing of 10 vials (380mg) of digoxin antibodies should be administered and repeated as necessary, with supportive measures. When the overdose is due to chronic digoxin administration of smaller doses and symptoms are critical, the standard dose is two vials (76mg).

Further Reading:

  1. Gibson PR, Shepherd SJ. Evidence-based dietary management of functional gastrointestinal symptoms: The FODMAP approach. J Gastroenterol Hepatol. 2010; 25(2): 252–8.
  2. Shepherd SJ, Parker FC, Muir JG, Gibson PR. Dietary triggers of abdominal symptoms in patients with irritable bowel syndrome: randomized placebo-controlled evidence. Clin Gastroenterol Hepatol. 2008; 6(7): 765–71.

References:

  1. Digestive Health Foundation. Irritable Bowel Syndrome. 2nd ed. Sydney: Gastroenterological Society of Australia; 2003.
  2. Gastrointestinal Expert Group. Therapeutic Guidelines: Gastrointestinal. Version 5. Melbourne: Therapeutic Guidelines Limited; 2011.
  3. Irritable Bowel Information & Support Association of Australia Inc. IBIS Irritable Bowel Information. Forest Lake, Australia. Available from http://www.ibis-australia.org. Accessed 13 Mar 2014.
  4. Shepherd Works. Hydrogen Breath Testing. Box Hill: Shepherd Works; 2014. Available from http://shepherdworks.com.au/disease-information/hydrogen-breath-testing. Accessed 13 Mar 2014.
  5. Shepherd Works. Low FODMAP Diet. Box Hill: Shepherd Works; 2014. Available from http://shepherdworks.com.au/disease-information/low-fodmap-diet. Accessed 13 Mar 2014.

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