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:
Intravenous:
In-Phos: 40 mL
Hyper-Phos-K: 15 mL
Oral:
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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