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ABNORMAL SERUM CALCIUM & PHOSPHATE LEVELS
Hypercalcemia causes central nervous system depression, includ-ing 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 hypervitamino-sis D, sarcoidosis, thyrotoxicosis, milk-alkali syndrome, adrenal insufficiency, and immobilization. With the possible exception of hypervitaminosis D, the latter disorders seldom require emergency lowering of serum calcium. A number of approaches are used to manage the hypercalcemic crisis.
In hypercalcemia of sufficient severity to produce symptoms, rapid reduction of serum calcium is required. The first steps include rehydration with saline and diuresis with furosemide, although the efficacy of furosemide in this setting has not been proved and use of the drug for this purpose appears to be falling out of favor. Most patients presenting with severe hypercalcemia have a substantial component of prerenal azotemia owing to dehy-dration, which prevents the kidney from compensating for the rise in serum calcium by excreting more calcium in the urine. Therefore, the initial infusion of 500–1000 mL/h of saline to reverse the dehydration and restore urine flow can by itself sub-stantially lower serum calcium. The addition of a loop diuretic such as furosemide following rehydration enhances urine flow and also inhibits calcium reabsorption in the ascending limb of the loop of Henle . Monitoring of central venous pressure is important to forestall the development of heart failure and pulmonary edema in predisposed subjects. In many subjects, saline diuresis suffices to reduce serum calcium to a point at which more definitive diagnosis and treatment of the underlying condi-tion can be achieved. If this is not the case or if more prolonged medical treatment of hypercalcemia is required, the following agents are available (discussed in order of preference).
Pamidronate, 60–90 mg, infused over 2–4 hours, and zoledronate, 4 mg, infused over at least 15 minutes, have been approved for the treatment of hypercalcemia of malignancy and have largely replaced the less effective etidronate for this indication. The bis-phosphonate effects generally persist for weeks, but treatment can be repeated after a 7-day interval if necessary and if renal function is not impaired. Some patients experience a self-limited flu-like syndrome after the initial infusion, but subsequent infusions gen-erally do not have this side effect. Repeated doses of these drugs have been linked to renal deterioration and osteonecrosis of the jaw, but this adverse effect is rare.
Calcitonin has proved useful as ancillary treatment in some patients. Calcitonin by itself seldom restores serum calcium to normal, and refractoriness frequently develops. However, its lack of toxicity permits frequent administration at high doses (200 MRC units or more). An effect on serum calcium is observed within 4–6 hours and lasts for 6–10 hours. Calcimar (salmon calcitonin) is available for parenteral and nasal administration.
Gallium nitrate is approved by the FDA for the management of hypercalcemia of malignancy. This drug inhibits bone resorption.At a dosage of 200 mg/m2 body surface area per day given as a continuous intravenous infusion in 5% dextrose for 5 days, gallium nitrate proved superior to calcitonin in reducing serum calcium in cancer patients. Because of potential nephrotoxicity, patients should be well hydrated and have good renal output before starting the infusion.
Because of its toxicity, plicamycin (mithramycin) is not the drug of first choice for the treatment of hypercalcemia. However, when other forms of therapy fail, 25–50 mcg/kg of plicamycin given intravenously usually lowers serum calcium substantially within 24–48 hours. This effect can last several days. This dose can be repeated as necessary. The most dangerous toxic effect is sudden thrombocytopenia followed by hemorrhage. Hepatic and renal toxicity can also occur. Hypocalcemia, nausea, and vomiting may limit therapy. Use of this drug must be accompanied by care-ful monitoring of platelet counts, liver and kidney function, and serum calcium levels.
Intravenous phosphate administration is probably the fastest and surest way to reduce serum calcium, but it is a hazardous proce-dure if not done properly. Intravenous phosphate should be used only after other methods of treatment (bisphosphonates, calci-tonin, and saline diuresis) 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 sud-den 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 sodium or potassium salts. Amounts required to provide 1 g of elemental phosphorus are as follows:
In-Phos: 40 mL
Hyper-Phos-K: 15 mL
Fleet Phospho-Soda: 6.2 mL
Neutra-Phos: 300 mL
K-Phos-Neutral: 4 tablets
Glucocorticoids have no clear role in the immediate treatment of hypercalcemia. However, the chronic hypercalcemia of sarcoidosis, vitamin D intoxication, and certain cancers may respond within several days to glucocorticoid therapy. Prednisone in oral doses of 30–60 mg daily is generally used, although equivalent doses of other glucocorticoids are effective. The rationale for the use ofglucocorticoids in these diseases differs, however. The hypercal-cemia of sarcoidosis is secondary to increased production of 1,25(OH)2D, possibly by the sarcoid tissue itself. Glucocorticoid therapy directed at the reduction of sarcoid tissue results in resto-ration of normal serum calcium and 1,25(OH)2D levels. The treatment of hypervitaminosis D with glucocorticoids probably does not alter vitamin D metabolism significantly but is thought to reduce vitamin D-mediated intestinal calcium transport. An action of glucocorticoids to reduce vitamin D-mediated bone resorption has not been excluded, however. The effect of glucocor-ticoids on the hypercalcemia of cancer is probably twofold. The malignancies responding best to glucocorticoids (ie, multiple myeloma and related lymphoproliferative diseases) are sensitive to the lytic action of glucocorticoids. Therefore part of the effect may be related to decreased tumor mass and activity. Glucocorticoids have also been shown to inhibit the secretion or effectiveness of cytokines elaborated by multiple myeloma and related cancers that stimulate osteoclastic bone resorption. Other causes of hypercalcemia—particularly primary hyperparathyroidism—do not respond to glucocorticoid therapy.
The main features of hypocalcemia are neuromuscular—tetany, paresthesias, laryngospasm, muscle cramps, and seizures. The major causes of hypocalcemia in the adult are hypoparathyroid-ism, vitamin D deficiency, chronic kidney disease, and malabsorp-tion. Hypocalcemia can also accompany the infusion of potent bisphosphonates and denosumab for the treatment of osteopo-rosis, but this is seldom of clinical significance unless the patient is already hypocalcemic at the onset of the infusion. Neonatal hypocalcemia is a common disorder that usually resolves without therapy. The roles of PTH, vitamin D, and calcitonin in the neo-natal syndrome are under investigation. Large infusions of citrated blood can produce hypocalcemia secondary to the formation of citrate-calcium complexes. Calcium and vitamin D (or its metab-olites) form the mainstay of treatment of hypocalcemia.
A number of calcium preparations are available for intrave-nous, intramuscular, and oral use. Calcium gluceptate (0.9 mEq calcium/mL), calcium gluconate (0.45 mEq calcium/mL), and calcium chloride (0.68–1.36 mEq calcium/mL) are available for intravenous therapy. Calcium gluconate is preferred because it is less irritating to veins. Oral preparations include calcium carbon-ate (40% calcium), calcium lactate (13% calcium), calcium phos-phate (25% calcium), and calcium citrate (21% calcium). Calcium carbonate is often the preparation of choice because of its high percentage of calcium, ready availability (eg, Tums), low cost, and antacid properties. In achlorhydric patients, calcium carbonate should be given with meals to increase absorption, or the patient should be switched to calcium citrate, which is somewhat better absorbed. Combinations of vitamin D and calcium are available, but treatment must be tailored to the individual patient and the individual disease, a flexibility lost by fixed-dosage combinations.
Treatment of severe symptomatic hypocalcemia can be accom-plished with slow infusion of 5–20 mL of 10% calcium gluconate. Rapid infusion can lead to cardiac arrhythmias. Less severe hypocalcemia is best treated with oral forms sufficient to provide approximately 400–1200 mg of elemental calcium (1–3 g calcium carbonate) per day. Dosage must be adjusted to avoid hypercalcemia and hypercalciuria.
When rapidity of action is required, 1,25(OH)2D3 (calcitriol), 0.25–1 mcg daily, is the vitamin D metabolite of choice because it is capable of raising serum calcium within 24–48 hours. Calcitriol also raises serum phosphate, although this action is usually not observed early in treatment. The combined effects of calcitriol and all other vitamin D metabolites and analogs on both calcium and phosphate make careful monitoring of these mineral levels especially important to prevent ectopic calcification sec-ondary to an abnormally high serum calcium × phosphate prod-uct. Since the choice of the appropriate vitamin D metabolite or analog for long-term treatment of hypocalcemia depends on the nature of the underlying disease, further discussion of vitamin D treatment is found under the headings of the specific diseases.
Hyperphosphatemia is a common complication of renal failure and is also found in all types of hypoparathyroidism (idiopathic, surgical, and pseudohypoparathyroidism), vitamin D intoxica-tion, and the rare syndrome of tumoral calcinosis (usually due to insufficient bioactive FGF23). Emergency treatment of hyper-phosphatemia is seldom necessary but can be achieved by dialysis or glucose and insulin infusions. In general, control of hyperphos-phatemia involves restriction of dietary phosphate plus phosphate-binding gels such as sevelamer and calcium supplements. Because of their potential to induce aluminum-associated bone disease, aluminum-containing antacids should be used sparingly and only when other measures fail to control the hyperphosphatemia. In patients with chronic kidney disease enthusiasm for the use of large doses of calcium to control hyperphosphatemia has waned because of the risk of ectopic calcification.
Hypophosphatemia is associated with a variety of conditions, including primary hyperparathyroidism, vitamin D deficiency, idiopathic hypercalciuria, conditions associated with increased bioactive FGF23 (eg, X-linked and autosomal dominant hypo-phosphatemic rickets and tumor-induced osteomalacia), other forms of renal phosphate wasting (eg, Fanconi’s syndrome), over-zealous use of phosphate binders, and parenteral nutrition with inadequate phosphate content. Acute hypophosphatemia may cause a reduction in the intracellular levels of high-energy organic phosphates (eg, ATP), interfere with normal hemoglobin-to-tissue oxygen transfer by decreasing red cell 2,3-diphosphoglycerate levels, and lead to rhabdomyolysis. However, clinically significantacute effects of hypophosphatemia are seldom seen, and emer-gency treatment is generally not indicated. The long-term effects of hypophosphatemia include proximal muscle weakness and abnormal bone mineralization (osteomalacia). Therefore, hypo-phosphatemia should be avoided when using forms of therapy that can lead to hypophosphatemia (eg, phosphate binders, certain types of parenteral nutrition) and treated in conditions that cause hypophosphatemia, such as the various forms of hypophos-phatemic rickets. Oral forms of phosphate are listed above.
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