Evidence-Based Treatment of Hypercalcemia

R. Daniel Hagerty

Disclosures

AccessMedicine from McGraw-Hill 

Background

Hypercalcemia is defined as plasma [Ca2+] greater than 10.5 mg/dl (or an ionized calcium level greater than 2.7 mmol/L). Emergency department patients will commonly present with mild, asymptomatic elevations usually not greater than 11 mg/dl. However, more significant levels of hypercalcemia are occasionally seen in emergency department patients with underlying malignancy or hyperparathyroidism. Signs and symptoms may include generalized weakness, dehydration, headaches, confusion/coma, bone pain, hypertension, QT shortening on ECG, abdominal pain, nausea, vomiting and kidney stones. Treatment strategies for hypercalcemia are geared toward rehydration, reducing calcium production and enhancing elimination. For decades, the standard of care for emergency treatment of hypercalcemia focused on saline hydration coupled with administration of furosemide to promote calciuresis. However, a recent, comprehensive literature review of the evidence for the use of furosemide vs. evidence for the use of bisphosphonates as primary treatment for hypercalcemia found little support for the current standard of care.[1]

Methods

The authors used Ovid Medline to search for human trials on hypercalcemia and furosemide from 1950 to April 2008, and articles related to bisphosphonates and hypercalcemia during the same period. Evidence-based Medicine Reviews and the Cochrane Database were also searched. In addition, available online textbooks were reviewed for recommendations on treatment of hypercalcemia.

Results

The search yielded only 9 studies (case series/case reports) on the use of furosemide in hypercalcemia. A total of 37 patients (39 treatment episodes) were included in 5 case series and 4 single case reports. The average dose of Lasix was 1,120 mg over a 24 hour period requiring intensive monitoring and careful replacement of urinary volume and electrolyte losses every 2-4 hours. Only 36% of these patients reached eucalcemia, and therapy was required for 6 to 12 days to reach the treatment goal.

In contrast to the results for furosemide, the authors found 34 randomized, controlled studies with a combined total of more than 1,000 patients evaluating the efficacy of hydration and bisphosphonate use in treating hypercalcemia. These studies showed greater than 70% success rate for normalization of calcium levels with only minimal side effects. As the onset of osteoclastic calcium blockage by bisphosphonates is 48 hours on average, results of the therapy will not likely be seen in the ED but during the sub-acute phase. The most recent studies available showed superiority of IV zoledronic acid (4 mg IV over 15 minutes) or pamidronate (60 mg IV over 2 hours) among the bisphosphonates. In addition, the authors found evidence for the use of calcitonin in combination with a bisphosphonate in severe cases of hypercalcemia. Calcitonin has been shown to decrease serum calcium in as little as 2 hours[1,2] and is recommended by the authors for severe cases and emergent management.

Relevance to Emergency Medicine

This study suggests some important points not only about the emergency treatment of hypercalcemia, but also about how we formulate and review therapies in general.

The authors' literature review found improved outcomes with hydration and bisphosphonate therapy for hypercalcemia. In contrast, the few studies of loop diuretics performed over the last 50 years demonstrated minimal success in spite of prolonged treatment, and significant associated complications. In light of this data, emergency physicians should re-evaluate their therapy and strongly consider hydration with administration of bisphosphonates and possibly calcitonin in the emergent treatment of symptomatic (12 mg/L < [Ca2+] < 14 mg/L) and severe ([Ca2+] > 14 mg/L) hypercalcemia. As dehydration is common, isotonic saline hydration upwards of 5L should still be considered the mainstay of therapy in the acute phase. Severe cases of hypercalcemia may also require the use of calcitonin (4 U/kg SQ), with a reduction in serum calcium seen in as little as 2 hours after administration. Bisphosphonates (zoledronic acid 4 mg IV over 15 minutes) should also be given to improve the subacute phase of treatment.

Perhaps equally important is the concept underlying this simple study. In today's practice of evidence-based medicine, physicians must continually question and re-evaluate common or 'time-honored' practices in an effort to improve patient care. Consider, for example, the patients who have benefited from the invalidation of the common practice of withholding opiate pain medications from those with suspected appendicitis until after examination by a surgeon, based on the evidence that physical exam findings are, in fact, not masked by making patients more comfortable. In the case of treating hypercalcemia, while the lack of or minimal amount of research for a therapy (e.g. use of loop diuretics for hypercalcemia) does not, in itself, necessarily invalidate that treatment, it should motivate further research into the area or at least cause physicians to question the treatment in comparison to other options available. When it exists, objective evidence should guide therapy. In the case of hypercalcemia, this study found that the generally accepted, and still recommended in many text books, 'standard of care' treatment with loop diuretics is based on Level C recommendations, anecdotal evidence, and in some cases 'historical precedent and common practice' in contrast to Class I and Level A evidence supporting hydration, bisphosphonates and calcitonin. Only by continued practice of the principles of evidence-based medicine can we change the standards of care and, over time, improve care of patients.

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