Monday, April 15, 2013

Digoxin, Potassium and Calcium


Very little of what we do on a daily basis, as pharmacists, fit into discrete silos.  In contrast to our didactic education (or mine, at least), chapters are studied focusing on specific disease states, medication classes are analyzed individually and cases are discussed with rarely more than one problem.  Of course learning to walk before you run through study and comprehension of the basic components and methods of problem solving is critical. However, it leaves one to their own devices, or post-graduate training, to synthesize not just knowledge but understanding how various different elements of a problem may change your treatment plan.

As the textbooks go, in the setting of hyperkalemia, insulin-dextrose, sodium bicarbonate, albuterol, sodium polystyrene sulfonate, and calcium are appropriate treatment strategy in combination.  However, in a similar setting of hyperkalemia associated with digoxin therapy, caution is advised when considering calcium. The basis of this is theoretical: additional calcium with an already increased intracellular concentration of calcium leading to altered contraction of myofibrils, delayed conduction and/or altered sarcoplasmic reticulum and mitochondrial functioning.  The evidence supporting this theory is often questioned due to its age (articles dating back to 1930s, see below) as well as more recent investigations have not associated with the administration of calcium in this setting with deleterious effects.  Such a clinical controversy yields a precarious dilemma when discussing the role of calcium in this setting, often dividing a room full of clinicians.

But more on the practical side of things, the role of calcium becomes less clear in the hypothetical clinical scenario where you may have a patient with signs and symptoms consistent with severe hyperkalemia (ecg changes, hemodynamic instability and generalized weakness) but the picture could be attributed to not just the patient’s digoxin, but also a CCB like verapamil or a beta-blocker as well. A broad spectrum approach is employed including transcutaneous pacing and DigiFAB administered empirically with a hyperkalemia cocktail, except for the calcium.  With few lab results back including a potassium of 9, twenty minutes later and still no change in the patient’s condition, is it now time for calcium? 

Operating in the silo of hyperkalemia in the setting of digoxin, it would seem risky based on the theory.  However, parallel to other situations, while there may be similarities between real life cases and text book learning, often there are other difficult to predict confounding elements.  Acknowledging the risks of calcium, but also understanding the evidence both of the literature and each given patient scenario that make up those real life confounders, calcium can be seen as a reasonable option.
In my experience instances in which DigiFAB was needed and calcium was concomitantly administered, . In two situations, it was not known that the patient was taking digoxin at the time of calcium administration and the other patient was known to be taking digoxin.  In all three situations, calcium did not lead to “stone-heart,” and seemed to help.  It should be said that theory behind the caution makes sense, and calcium should be considered with caution, if not withheld, in situations where digoxin is known to be involved. But, as described, and often encountered, it isn’t always that simple. 

Gold H, Edwards DJ. The effects of ouabain on heart in the presence of hypercalcemia. Am Heart J. 1927;3:45-50.
Lieberman AL. Studies on calcium VI: some interrelationships of the cardiac activities of calcium gluconate and scillaren-B. J Pharmacol Exp Ther. 1933;47:183-192
Bower JO, Mengle HAK. The additive effect of calcium and digitalis. JAMA. 1936;106:1151-1153
Smith PK, Winkler AW, Hoff HE. Calcium and digitalis synergism: the toxicity of calcium salts injected intravenously into digitalized animals. Arch Intern Med. 1939;64:322-328
Nola GT, Pope S, Harrison DC. Assessment of the synergistic relationship between serum calcium and digitalis. Am Heart J. 1970;79:499-507
Wagner J, Salzer WW. Calcium-dependent toxic effects of digoxin in isolated myocardial preparations. Arch Int Pharmacodyn. 1976;223:4-14
Khatter JC, Agbanyo M, Navaratnam S, et al. Digitalis cardiotoxicity: cellular calcium overload as a possible mechanism. Basic Res Cardiol. 1989;84:553-563
Kne T, Brokaw M, Wax P. Fatality from calcium chloride in a chronic digoxin toxic patient (abstract). J Toxicol Clin Toxicol. 1997;5:505

6 comments:

  1. Absolutely love the blog. Wonderful articles, well researched, and well written. Thank you. Wanted to share one reference that also found no support that calcium administration is contraindicated in dig toxic patients after completing a chart review spanning 17.5 years involving 23 patients.


    Levine M, Nikkanen H, Pallin DJ. The effects of intravenous calcium in patients with digoxin toxicity.J Emerg Med. 2011 Jan;40(1):41-6.

    Once again, thank you for presenting wonderful insight on a variety of ED topics.

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  2. Thank you for your kind words, and for providing this additional reference. If you have any questions or if you would like to see something discussed on this blog, please feel free to contact us and we'll do our best to address the topic.

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    1. Would love to see a discussion regarding your experiences with push dose pressors (e.g., phenylephrine)- doses used, response seen, subsequent dosing, etc...and second, a discussion on chemical restraint for ED patients who are absolutely out of control.

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  3. I find you blog to be a well of very useful, brief and informative reviews that are of great assistance in day to day practice. Thank you very much.

    Also great to see the list of your friendly blogs that include the "gold standard" for reading on today's EM.

    On the hyperkalemia topic, there has been a stream of opinions and publications on SPSP dangers and efficiency (or lack thereof)... What is your opinion on that?

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  4. Thank you for your comment.

    With regards to efficacy and dangers associated with SPS, there have indeed been a number of opinions regarding its use in the management of hyperkalemia. EMCrit has a fantastic podcast regarding this topic, which can be found here:

    http://emcrit.org/misc/is-kayexalate-useless/

    We do fall under the assumption that patients need the "hyperkalemia cocktail" when they present with elevated K levels that may or may not be associated with EKG changes, and some centers do have order sets that consist of what is typically used for the management of hyperkalemia: IV calcium (gluconate or chloride), insulin with or without dextrose, sodium bicarbonate, loop diuretics, albuterol, and SPS. It makes it too easy to fall under the trap of clicking off everything within the order set without really thinking about the true need for all of these therapies in every patient.

    Keeping in mind that it takes at least two hours before the effects of SPS are manifested in lowering the K level in the setting of hyperkalemia, along with the reports of variable efficacy and the dangers of colonic ischemia and necrosis, I think it would be worthwhile to hold off on ordering it immediately for patients. Re-evaluation of patients is warranted after initial treatment options have been administered, and I think at that point, it would be reasonable to determine if SPS is truly necessary based on the repeat K level, signs and symptoms (including EKG changes), and underlying cause(s) (if determined) of hyperkalemia.

    Just my two cents.

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