Does Furosemide Have a Role in the Management of Hypercalcemia?

IN RESPONSE:

Dr. Robey and colleagues question our conclusion that furosemide has no role other than management of fluid overload; however, we are not alone in this conclusion (1–3; http://www.uptodateonline.com). The fact that furosemide produces calciuria is not in question. The question is whether this translates into a practical therapy for malignant hypercalcemia. What we found was not a “wealth,” but a paucity of evidence for the value of furosemide and no evidence to support the currently recommended doses. The other key element in the case reports was the intensity of monitoring to ensure adequate rehydration and replacement of urine loss, which is certainly not standard today and would substantially increase the cost of therapy. Only one third (not an “overwhelming majority”) of patients achieved normalized calcium levels, with duration of response not reported. The goal of therapy should be a normal—not just improved—calcium level.

Dr. Robey and colleagues overstate the toxicity of the single dose of bisphosphonates required for hypercalcemia. Toxicity is minimal—typically fever—and in the acute care setting, it is administered on an inpatient basis, so access to the medications is not an issue. The toxicity and cost issues noted are a concern for long-term rather than short-term use. Delaying institution of bisphosphonates prolongs length of stay and might outweigh any cost advantage, although no comparison studies have been published. Withholding bisphosphonates may result in rapid relapse once hydration is stopped, particularly in a palliative setting in which disease-specific therapy may not exist.

Although I agree that one could conduct a randomized trial of bisphosphonates with and without furosemide, there are too many unanswered questions to ethically proceed. What dose of furosemide would one use? What evidence would determine this dose? Would you conduct phase I trials to determine the appropriate dose first? How would one determine adequate hydration in the furosemide group? There are many more critical things to research and newer therapies under evaluation as we continue to understand the cytokines involved in malignant hypercalcemia. Teach fluids and bisphosphonates; they are easy to learn and have less potential for harm from over- or underhydration.