Nefarious Hypercalcemia
Author: Daniel Cabrera, M.D. / Reviewer: Cameron Wangsgard, M.D.
Why is this important?
Emergency Physicians are experts on the management of life-threatening electrolyte abnormalities, particularly related to potassium and sodium. Although relatively common affecting between 5 and 7.5% of the population in the Emergency Department (ED)(1), calcium related emergencies receive little attention despite having the potential for significant morbidity and mortality.
Hypercalcemia as defined as a total serum calcium level greater than 10mg/dL or greater than 5.6mg/dL as an ionized form (see albumin corrected calcium formula here). In a somewhat arbitrary fashion severe or critical hypercalcemia is defined as a greater than 14mg/dL or 10mg/dL ionized(2). While the most common etiology in outpatient population is primary hyperparathyroidism, in hospitalized and ED patients, malignancy related hypercalcemia is very common, along with uremia and sepsis(1).
The post is focused on the management of malignancy related hypercalcemia.
How can I diagnose it?
Clinically significant hypercalcemia in the ED will be most likely related to malignancy, particularly in severe cases. The main problem to diagnose hypercalcemia is the fact that it usually flies under our radar as the symptoms related to it are often non-specific and can be explained by other problems, like the cancer itself, chemotherapy effects, or infection. Classic presentation includes weakness, altered mental status, nausea, constipation and polyuria; all of which correlate to the degree of hypercalcemia and the rate of onset(3). In severe cases, hypercalcemia can lead to bradyarrhythmias, AV block and even cardiac arrest(2). As diagnosis can be slippery, it is probably prudent to obtain a calcium level in oncologic patients presenting non focal symptoms and also in non-oncologic patients with altered mental status, unexplained weakness, or generalized symptoms with no obvious etiology.
The physiopathology of cancer related hypercalcemia is explained by four mechanisms(2):
- Para-thyroid hormone related peptide (PTHrP). The most common, accounting for up to 80% of the cases.
- Osteoclastic metastatic lesions. Classically presenting with associated localized bone-pain.
- Vitamin-D secretion. Rare presentation, often related to lymphatic neoplasms.
- PTH secretion. Very rare.
Once the suspicion of hypercalcemia is made, the diagnosis is relatively simple. A total or ionized calcium will be enough to make the diagnosis. Given the comorbidities these patients commonly have, a full set of electrolytes and an albumin level is probably reasonable to obtain as well. Although not necessary to make the diagnosis and of little value in the ED, ordering a PTHrP will help the admitting team (high levels of PTHrP predict resistance to bisphosphonates). Another clue that may help in the diagnosis is a narrow QRS and a short QT in an ECG.
How do I approach the treatment of a patient with hypercalcemia?
The first goal in the treatment of hypercalcemia, particularly in severe cases, is aggressive volume resuscitation. High calcium levels are usually accompanied of hypovolemia, secondary to the diluting effect of calcium in urine, with water deficits as large as 10L(2). Normal saline administration, with an initial bolus of 1-2L is the first step and commonly will be the single most important tier in the treatment.
Although commonly mentioned, the use of loop diuretics (e.g., furosemide) have been under increased scrutiny as it appears only marginally effective and above all, it is likely to worsen the hypovolemia. Currently loop diuretics are only recommended in patients with volume overload(4).
Bisphosphonates should be consider early in the treatment of patients with moderate to severe hypercalcemia of malignancy(5). These medications has been not routinely used in the ED given its long infusion times and slow onset of action on calcium metabolism. However, newer and more potent bisphosphonates such as zolendronic acid have a short infusion time and effects can be observed within few hours. Severe or very symptomatic hypercalcemia probably warrants use of zolendronic acid as early as possible.
Multiple other medications, such as calcitonin, mythramycin and gallium nitrate are commonly describe in the management of hypercalcemia, but currently their benefits are at most minimal and routine use is not advised.
Glucocorticoids are effective in Vitamin-D producing tumors like lymphomas. In very severe cases of hypercalcemia; hemodialysis may be required.
References
- Lee C-T, Yang C-C, Lam K-K, Kung C-T, Tsai C-J, Chen H-C. Hypercalcemia in the emergency department. Am J Med Sci. 2006;331(3):119–23.
- Wagner J, Arora S. Oncologic metabolic emergencies. Emerg Med Clin North Am. 2014 Aug;32(3):509–25.
- Halfdanarson TR, Hogan WJ, Moynihan TJ. Oncologic emergencies: diagnosis and treatment. Mayo Clinic Proceedings [Internet]. Elsevier; 2006 [cited 2014 Apr 21]. p. 835–48. Available from: http://www.sciencedirect.com/science/article/pii/S0025619611617400
- LeGrand SB, Leskuski D, Zama I. Narrative Review: Furosemide for Hypercalcemia: An Unproven yet Common Practice. Ann Intern Med. 2008 Aug 19;149(4):259–63.
- Ziegler R. Hypercalcemic crisis. J Am Soc Nephrol. 2001;12(suppl 1):S3–9.
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The data behind zoledronic acid being superior to other agents like pamidronate is a little questionable. (1) The infusion time as a convenience issue is likely irrelevant for anyone sick enough to require admission (2) These agents take days to work! In the primary study comparing the two (J Clin Oncol 2001;19:558-67) there was no statistically significant difference in the percentage of complete responders at 4 days (their first measured timepoint) between the pamidronate group and the zoledronic acid 4 mg group; the difference was shown with the zoledronic acid 8 mg dose, which is not what is currently approved/recommended in the US. For outpatient chemo infusion centers, therapy with zoledronic acid makes sense because the infusion time can be much more convenient. However, in the ED this is not likely to make as much of a difference. I'm still pretty comfortable recommending pamidronate in the ED for this indication, and we've restricted zoledronic acid to outpatient/infusion clinic use only.
Excellent point Meghan.<br />
The main benefit of Zoledronic over Pamidronate is the infusion time, but you well point that maybe irrelevant in the big scheme of ED LOS, but I think the 15\' infusion time maybe beneficial in patients with sever hypercalcemia.<br />
Bottom line I agree that Pamidronate is a good option.<br />