Effective management of hypercalcemia demands consideration of both the patient’s immediate, as well as longer-term, clinical situation in light of the patient’s prognosis. The primary aim in the acute management of hypercalcemia is to normalize serum values and decrease symptoms. However, this must be done with appreciation that the metabolic derangement was generated by an underlying malignancy. The main focus of clinical therapeutics should be aimed at this.
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A computer-generated image of multinucleated osteoclasts etching away the trabecular bone in a process called bone resorption. The bisphosphonates inhibit this process in malignancy-induced hypercalcemia.
Review of the Data
Intravenous (IV) fluids. IV hydration with isotonic saline represents the most immediate and critical intervention in the acute management of malignant hypercalcemia. This condition has multiple, potentially deleterious effects on the kidney, including vasoconstriction, inhibition of salt absorption distally, and antagonism of anti-diuretic hormone (ADH), leading to both salt and water loss. The decrease in intravascular volume then potentiates increased sodium re-absorption proximally in the kidney.
Isotonic saline restores the volume depletion that invariably occurs in the setting of hypercalcemia-provoked urinary salt wasting. The restoration of intravascular volume results in an increase in the glomerular filtration rate and, thus, an increase in calcium filtration. Furthermore, proximal tubular sodium and calcium re-absorption decrease as the glomerular filtration rate increases. Additionally, an increase in sodium and water presentation to the distal renal tubular sites provokes a further calciuresis.
It is estimated that with saline hydration, the calcium concentration should decline, at least by the degree to which dehydration raised it, typically in the range of 1.6 mg to 2.4 mg per deciliter.4 Hydration alone, however, rarely leads to normalization of the serum calcium concentration in patients with severe hypercalcemia.
The rate of infusion is based on the severity of hypercalcemia, and the patient’s age and comorbidities, with particular attention to cardiac or renal disease. A standard approach for most patients without edema and without heart or renal failure is to begin a saline infusion at an initial rate between 200 mL/h to 300 mL/h. The goal is to maintain urine output at 100 mL/h to 150 mL/h.
Furosemide. Following the administration of intravenous fluids to re-establish a euvolemic state, furosemide historically has been used because it has a calcinuric effect with forced diuresis. It also is useful for managing and preventing the fluid overload that occurs with saline hydration. However, data does not support its routine use to lower calcium levels in hypercalcemic patients.
The majority of articles studying the use of furosemide were published in the 1970s and ’80s, and they involve a variety of doses and administration schedules ranging from 40 mg orally daily to 100 mg IV hourly with variable improvement in serum calcium levels and effects that were short-lived. Although some studies have shown that these high doses (2,400 mg/24 hours) of furosemide can decrease calcium levels, resultant severe metabolic derangements in other electrolytes were encountered. This approach required frequent and invasive monitoring to prevent such derangements.5 The clinical application of these studies have led to published recommendations that are as variable as the doses used in the initial studies more than 30 years ago.
This includes the consideration that, in light of the availability and efficacy of bisphosphonates, furosemide might no longer be clinically helpful in this endeavor.6 The current role of furosemide in the management in hypercalcemic patients remains on an as-needed basis for management of fluid overload states brought about after aggressive IV fluid resuscitation.
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Figure 1: Diagnostic Approach to Hypercalcemia.