Calcium therapy hypercalcemia with

Adams J, Diz M, Sharma O. Effective reduction in the serum 1,25-dihydrox-y vitamin D and calcium concentration in sarcoidosis associated hypercalcemia with short course of chloroquine therapy. Ann Intern Med 1989 111 437-438. 

Because the severity of symptoms and the absolute serum concentration are poorly correlated in some patients, institution of therapy should be dictated by the clinical scenario. All patients with hypercalcemia should be treated with aggressive rehydration normal saline at 200 to 300 mL/hour is a routine initial fluid prescription. For patients with mild hypocalcemia, hydration alone may provide adequate therapy. The moderate and severe forms of hypercalcemia are more likely to have significant manifestations and require prompt initiation of additional therapy. These patients may present with anorexia, confusion, and/or cardiac manifestations (bradycardia and arrhythmias with ECG changes). Total calcium concentrations greater than 13 mg/dL (3.25 mmol/L) are particularly worrisome, as these levels can unexpectedly precipitate acute renal failure, ventricular arrhythmias, and sudden death. 

Hypercalcemia Carefully monitor standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine. Do not use loop diuretics until the patient is adequately rehydrated use with caution in combination with zoledronic acid in order to avoid hypocalcemia. Use zoledronic acid with caution with other nephrotoxic drugs. Concomitant use with estrogen/hormone replacement therapy (alendronate) Two clinical studies have shown that the degree of suppression of bone turnover (as assessed by mineralizing surface) was significantly greater with the combination than with either component alone. 

Plicamycin (mithramycin, Mithracin) is one of the chro-momycin group of antibiotics produced by Streptomyces tanashiensis. Plicamycin binds to DNA and inhibits transcription. It also inhibits resorption of bone by osteoblasts, thus lowering serum calcium levels. Very little is known about its distribution, metabolism, and excretion. Because of its severe toxicity, plicamycin has limited clinical utility. The major indication for plicamycin therapy is in the treatment of life-threatening hypercalcemia associated with malignancy. Plicamycin also can be used in the palliative therapy of metastatic testicular carcinoma when all other known active drugs have failed. 

Therapy with hydrochlorothiazide, up to 50 mg twice daily, or chlorthalidone, 50-100 mg daily, is recommended. Loop diuretics such as furosemide and ethacrynic acid should not be used because they increase urinary calcium excretion. The major toxicity of thiazide diuretics, besides hypokalemia, hypomagnesemia, and hyperglycemia, is hypercalcemia. This is seldom more than a biochemical observation unless the patient has a disease such as hyperparathyroidism in which bone turnover is accelerated. Accordingly, one should screen patients for such disorders before starting thiazide therapy and monitor serum and urine calcium when therapy has begun. 

A patient with psoriasis developed hypercalcemia and hypercalciuria after 28 days of treatment with tacalcitol (1208). He had been taking long-term thiazide therapy for his hypertension. When he used topical tacalcitol ointment his serum calcium concentration and urinary calcium excretion gradually increased to 3.55 mmol/1 and 0.475 g/day respectively. Within 7 days of withdrawal of tacalcitol, the serum calcium concentration had normalized. 

Hypercalcemia causes central nervous system depression, including coma, and is potentially lethal. Its major causes (other than thiazide therapy) are hyperparathyroidism and cancer with or without bone metastases. Less common causes are hypervitaminosis D, sarcoidosis, thyrotoxicosis, milk-alkali syndrome, adrenal insufficiency, and immobilization. With the possible exception of hypervitaminosis D, these latter disorders seldom require emergency lowering of serum calcium. A number of approaches are used to manage the hypercalcemic crisis. 

Giving intravenous phosphate is probably the fastest and surest way to reduce serum calcium, but it is a hazardous procedure if not done properly. Intravenous phosphate should be used only after other methods of treatment (pamidronate, calcitonin, saline diuresis with furosemide, and plicamycin) have failed to control symptomatic hypercalcemia. Phosphate must be given slowly (50 mmol or 1.5 g elemental phosphorus over 6-8 hours) and the patient switched to oral phosphate (1-2 g/d elemental phosphorus, as one of the salts indicated below) as soon as symptoms of hypercalcemia have cleared. The risks of intravenous phosphate therapy include sudden hypocalcemia, ectopic calcification, acute renal failure, and hypotension. Oral phosphate can also lead to ectopic calcification and renal failure if serum calcium and phosphate levels are not carefully monitored, but the risk is less and the time of onset much longer. Phosphate is available in oral and intravenous forms as the sodium or potassium salt. Amounts required to provide 1 g of elemental phosphorus are as follows ... 

The principal therapeutic concern is to restore normocalcemia and normophosphatemia. Under most circumstances, vitamin D (25,000-100,000 units three times per week) and dietary calcium supplements suffice. More rapid increments in serum calcium can be achieved with calcitriol, though it is not clear that this metabolite offers a substantial advantage over vitamin D itself for long-term therapy. Many patients treated with vitamin D develop episodes of hypercalcemia. This complication is more rapidly reversible with cessation of therapy using calcitriol rather than vitamin D. This would be of importance to the patient in whom such hypercalcemic crises are common. Dihydrotachysterol and 25(OH)D have not received much study as therapy for hypoparathyroidism, though both should be effective. Whether they offer advantages over vitamin D sufficient to justify their added expense remains to be seen. 

Since unresolved nephrocalcinosis may lead to residual abnormalities in the kidney including microscopic hematuria, hypercalcemia, and impaired tubular function [100,104,105], renal ultrasonography within a few months of initiating loop diuretics may be warranted [100 104]. If long-term diuretic therapy is needed, a thiazide diuretic alone or in combination with furosemide may reduce the risk of renal calcifications by decreasing urinary calcium and oxalate excretion [100,102,104,107,108]. However, two studies of premature infants failed to show a reduction in either urinary oxalate or calcium excretion when thiazides were added to furosemide therapy [107,109]. 

Active vitamin D therapy should be initiated in patients with Stage 3 or 4 CKD with oral calcitriol 0.25 meg per day or oral doxercalciferol 2.5 meg three times per week. Prior to starting therapy the serum calcium aud phosphorus should be well coutrolled (serum calcium <9.5 mg/dL aud phosphorus <4.6 mg/dL) to minimize the risk of hypercalcemia and an elevated Ca x P. In patients with Stage 5 CKD there is a clearly defined role for treatment with active vitamin D or a vitamin D analog since the conversion of precursors to active vitamin D is impaired. Dosing recommendations based on PTH are provided in Table 44—8. Serum calcium and Ca x P should be monitored regularly while the patient is receiving therapy. ... 

For those patients with normal to moderately impaired renal function, the cornerstone of initial treatment of hypercalcemia is volume expansion to increase urinary calcium excretion (see Table 49-6). Patients with severe renal insufficiency usually do not tolerate volume expansion they may be initiated on therapy with calcitonin. Patients with symptomatic hypercalcemia are often dehydrated secondary to vomiting and polyuria thus rehydration with saline-containing fluids is necessary to interrupt the stimulus for sodium and calcium reabsorption in the renal mbule. ° Rehydration can be accomplished by the infusion of normal saline at rates of 200 to 300 mL/h, depending on concomitant conditions (primarily cardiovascular and renal) and extent of hypercalcemia. Adequacy of hydration is assessed by measuring fluid intake and output or by central venous pressure monitoring. Loop diuretics such as furosemide (40 to 80 mg IV every 1 to 4 hours) or ethacrynic acid (for patients with sulfa allergies) may also be instiffited to increase urinary calcium excretion and to minimize the development of volume overload from the administration of saline (see Table 49-6). Loop diuretics such as furosemide... 

Mithramycin (plicamycin) is a potent cytotoxic antibiotic that inhibits osteoclast-mediated bone resorption and thereby reduces hypercalcemia. Mithramycin may be administered at a dose of 25 mcg/kg via intravenous infusion over 4 to 6 hours in saline or 5% dextrose solutions. This therapy may be repeated daily for 3 to 4 days or on alternating days for 3 to 8 doses. ° Serum calcium levels begin to fall within 12 hours of a mithramycin dose, with the peak effect generally occurring within 48 to 96 hours.Single doses are usually well tolerated. Adverse effects of mithramycin include nausea, vomiting, stomatitis, thrombocytopenia, inhibition of platelet function, and renal and hepatotoxicity. Because these adverse effects are more commonly associated with multiple doses, mithramycin is usually limited to short-term therapy in patients who have not responded to alternative therapies. Monitoring parameters include complete blood count, liver function, and renal function. Mithramycin should be avoided in patients with thrombocytopenia and liver and renal insufficiency. ... 

Once the hypercalcemic crisis has resolved, or in patients with milder calcium elevations, longterm therapy can be initiated. Parathyroidectomy remains the definitive therapy for primary hyperparathyroidism. As described below, a Ca mimetic that stimulates the CaSR is a promising therapy for hyperparathyroidism. If the hypercalcemia results from malignancy, therapy ideally is directed at the underlying cancer. When this is not possible, intermittent dosing of parenteral bisphosphonates has been used to keep serum Ca within an acceptable range. 

Calcitonin is often used in Paget s disease to control hypercalcemia. The answer is (D). Long-term therapy with glucocorticoids such as prednisone is associated with a reduction in bone mineral density and an increased risk of fractures. The other drugs are not known to have significant effects upon bone or serum calcium. The answer is (C). 

Following initiation of anti hypertensive therapy with thiazide diuretics, transient hypercalcemia has been seen in over one-third of patients (87). Two percent of patients receiving long-term thiazide diuretics administration had persistent hypercalcemia (68). In the elderly (especially women), combined administration of thiazides with vitamin 0 supplements (for osteoporosis) can have synergistic effects on the elevation of serum calcium levels resulting in severe hypercalcemia (69). Similarly, if the patient is predisposed to hypercalcemia (IHPT, 2HPT or immobilization), thiazides can precipitate significant and sustained hypercalcemia (68,70). 

Hypoparathyroidism has long been recognized as a disease which is difficult to manage with large doses of vitamin D and calcium supplements. Because the full effects of vitamin D are slow in both onset and reversal, considerable time may elapse before the action of a particular dose is established or the harmful effects of inadvertent overdose are relieved. 7 0.25—1.0 pg daily dose of la,25-dihydroxyvitamin D3 corrects the hypocalcemia of parathyroid insufficiency, and hypercalcemia resulting from overdose decreases quickly upon withdrawal of therapy. 

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