Calcium

More than 99% of total body calcium is found in bone; the remaining less than 1% is in the ECF and ICF. calcium plays a critical role in the transmission of nerve impulses, skeletal muscle contraction, myocardial contractions, maintenance of normal cellular permeability, and the formation of bones and teeth. There is a reciprocal relationship between the serum calcium concentration (normally 8.6-10.2 mg/dL [2.15-2.55 mmol/L]) and the serum phosphate concentration that is regulated by a complex interaction between parathyroid hormone, vitamin D, and calcitonin. About one-half of the serum calcium is bound to plasma proteins; the other half is free ionized calcium. Given that the serum calcium has significant protein binding, the serum calcium measurement must be corrected in patients who have low albumin concentrations (the major serum protein). The most commonly used formula adds 0.8 mg/dL (0.2 mmol/ L) of calcium for each gram of albumin deficiency as follows:

Corrected [Ca] = Measured [Ca mg/dL] + [0.8 x (4 - measured albumin g/dL)]

Note: To convert conventional units (mg/dL) to SI calcium units multiply by a factor of 0.25. To convert SI calcium units to conventional calcium units multiply by a factor of 4. To convert conventional albumin units (g/dL) to SI albumin units (g/dL) multiple by a factor of 10. To convert SI albumin units (g/dL) to conventional albumin units (g/ dL) divide by a factor of 2.

Hypocalcemia is caused by inadequate intake (vitamin deficiency, poor dietary calcium sources, alcoholism) or excessive losses (hypoparathyroidism, renal failure, al-kalosis, pancreatitis). Clinical manifestations of hypocalcemia are seen with total serum concentrations less than 6.5 mg/dL (1.63 mmol/L) or an ionized calcium of less than 1.12 mmol/L and include tetany, circumoral tingling, muscle spasms, hypoactive reflexes, anxiety, hallucinations, hypotension, myocardial infarction, seizures, lethargy, stupor, and Trousseau's sign or Chvostek's sign.32,37 Trousseau's sign is elicited by inflating a BP cuff on the patient's upper arm, whereby hypocalcemic patients will experience tetany of the wrist and hand as evidenced by thumb adduction, wrist flexion, and metacarpophalangeal joint flexion. Chvostek's sign is elicited by tapping on the proximal distribution of the facial nerve (adjacent to the ear). This will produce a brief spasm of the upper lip, eye, nose, or face in hypocalcemic patients. Ionized calcium concentrations are typically used to assess calcium status in the critically ill patient.

Causes of hypocalcemia include hypoparathyroidism, hypomagnesemia, alcoholism, hyperphosphatemia, blood product infusion (due to chelation by the citrate buffers), chronic renal failure, vitamin D deficiency, acute pancreatitis, alkalosis, and hy-poalbuminemia. In the setting of hypo-calcemia, magnesium concentration should be checked and corrected if low. Given that hypocalcemia may be caused by hypomag-nesemia, clinicians should be aware that the serum calcium concentrations may not normalize until serum magnesium is replaced. Medications that cause hypocalcemia include phosphate replacement products, loop diuretics, phenytoin (Dilantin, available as generic), phenobarbital (available as generic), corticosteroids, aminoglycoside antibiotics, and acetazolamide (available as generic).34,39,42

Oral calcium replacement products include calcium carbonate (OsCal, Glax-oSmithKline and various generics; Tums, GlaxoSmithKline and various generics) and calcium citrate (Citrical, Mission Pharmacal, and various generics). IV calcium replacement products include calcium gluconate and calcium chloride (both products available as generic). Calcium gluconate is preferred for peripheral use because it is less irritating to the veins; it may also be given intramuscularly. Each 10 mL of a 10% calcium gluconate solution provides 90 mg (4.5 mEq or 2.25 mmol) of elemental calcium. Calcium chloride is associated with more venous irritation and extravasation and is generally reserved for administration via central line. Each 10 mL of a 10% calcium chloride solution contains 270 mg (13.5 mEq or 6.75 mmol) of elemental calcium. IV calcium products are given as a slow push or added to 500 to 1,000 mL of

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0.9% normal saline for slow infusion. ' In addition to hypocalcemia, IV calcium may also be used for massive blood transfusions, calcium channel blocker overdose, and emergent hyperkalemia and hypermagnesemia.

For acute symptomatic hypocalcemia, 200 to 300 mg of elemental calcium is administered IV and repeated until symptoms are fully controlled. This is achieved by infusing 1 g of calcium chloride or 2 to 3 g of calcium gluconate at a rate no faster than 30 to 60 mg of elemental calcium per minute. More rapid administration is asso ciated with hypotension, bradycardia, or cardiac asystole. Total calcium concentration is commonly monitored in critically ill patients. Under normal circumstances, about half of calcium is loosely bound to serum proteins while the other half is free. Total calcium concentration measures bound and free calcium. Ionized calcium measures free calcium only. Under usual circumstances, a normal calcium concentration implies a normal free ionized calcium concentration. Ionized calcium should be obtained in patients with comorbid conditions that would lead to inconsistency between total calcium and free serum calcium (abnormal albumin, protein, or immunoglobulin concentrations). For chronic asymptomatic hypocalcemia, oral calcium supplements are given at doses of 2 to 4 g/day of elemental calcium. Many patients with calcium deficiency have concurrent vitamin D deficiency that must also be corrected in order to

2 37 38

restore calcium homeostasis.

Hypercalcemia is defined as a calcium concentration greater than 10.2 mg/dL (2.55 mmol/L). It may be categorized as mild if total serum calcium is 10.3 to 12 mg/dL (2.575-3 mmol/L), moderate if total serum calcium is 12.1 to 13 mg/dL (3.025-3.25 mmol/L), or severe when serum concentration is greater than 13 mg/dL (3.25 mmol/ L). Causes of hyper-calcemia include hyperparathyroidism, malignancy, Paget's disease, Addison's disease, granulomatous diseases (e.g., tuberculosis, sarcoidosis, or histoplasmosis), hyperthyroidism, immobilization, multiple bony fractures, acidosis, and milk-alkali syndrome. Multiple medications cause hypercalcemia and include thiazide diuretics, estrogens, lithium (available as generic), tamoxifen (Nolvadex, available as generic), vitamin A, vitamin D, and calcium supplements.2,33, 7,42

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 rehyd-ration: normal saline at 200 to 300 mL/h is a routine initial fluid prescription. For patients with mild hypercalcemia, 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 concentrations can unexpectedly precipitate acute renal failure, ventricular arrhythmias, and sudden death.

Once fluid administration has repleted the ECF, forced diuresis (with associated calcium loss) can be initiated with a loop diuretic. For this approach to be successful, normal kidney function is required. In renal failure patients, the alternative therapy is emergent hemodialysis. Other treatment options include bisphosphonates (zoledronic acid [Zometa, Novartis], pamidronate [Aredia, available as generic]), hydrocortisone (available as generic), mithramycin (Mithracin), calcitonin, and gallium. Given their efficacy and favorable side-effect profile, bisphosphonates are typically the agents of choice. Table 27—9 outlines the treatment options for hypercalcemia including time to

2 34 37 38

onset of effect, duration of effect, and efficacy. Phosphorus

Phosphorus is primarily found in the bone (80%—85%) and ICF (15%—20%): the remaining less than 1% is found in the ECF. Note that phosphorus is the major anion within the cells. Given this distribution, serum phosphate concentration does not accurately reflect total body phosphorus stores. Phosphorus is expressed in milligrams (mg) or millimoles (mmol), not as milliequivalents (mEq). Because phosphorus is the source of phosphate for adenosine triphosphate (ATP) and phospholipid synthesis, manifestations of phosphorus imbalance are variable.

Dietary intake, parathyroid hormone levels, and renal function are the major determinants of the serum phosphorus concentration, which is normally 2.7 to 4.5

mg/dL (0.87—1.45 mmol/L). ' Hypophosphatemia is defined by a serum phosphorus concentration less than 2.5 mg/dL (0.81 mmol/L); severe hypophosphatemia occurs when the phosphorus concentration is less than 1 mg/dL (0.323 mmol/L). Hypophosphatemia can be caused by increased distribution to the ICF (hyperglycemia, insulin therapy, or malnourishment), decreased absor ption (star vat ion, excessive use of phosphorus-binding antacids, vitamin D deficiency, diarrhea, or laxative abuse) or increased renal loss (diuretic use, diabetic ketoacidosis, alcohol ab-

38 39

use, hyperparathyroidism, or burns). ' Severe hypophosphatemia can result in impaired diaphragmatic contractility and acute respiratory failure. Medications that cause hypophosphatemia include diuretics (acetazolamide [Diamox, available as generic], furosemide [Lasix, available as generic], hydrochlorothiazide [Hydrodiur-il, available as generic]), sucralfate (Carafate, available as generic), corticosteroids, cisplatin (available as generic), antacids (aluminum carbonate, calcium carbonate, and magnesium oxide [antacids all available as generic]), foscarnet (Foscavir, Astra Zeneca), phenytoin (Dilantin, available as generic), phenobarbital (available as generic), and phosphate binders (sevelamer [Renvela, Genzyme Corp.], and calcium acetate [PhosLo, Nabi]).

Table 27-9 Selected Treatment Options for the Management of Hypercalcemia

Therapy

Dose

Onset

Ourïtion

iffiCKy

Normal s*line

3-âUîJa/

Hour;

Hour;

1-Î mg/tlL

FuruWiri^dMi*. ¿rtible ir> t>c?rt<?i¡0

80-160 rr*jAJ5y

Hüurí

HöurS

I-Î mo^dl

Hyiiacor tisane- (available as generic)

200 mg/diy

Hours

Days

h' ifcl/unp; editable

Calcitonin (MiarAkln, Njv'difK)

■t-B uniiVkg

Hour;

Hours

1-7 nnq/Llt

ti' il1 r m i rye il i \MiiMr.sc m!

35 rncíj/fc()

i? hour;

Oiyi

1 imtjAII

Pamidronate (Aredia, availabk? as -genwjc)

iO-SOin^'wei*

Days

ï-J weeks

l-S mgAlL

7rJedir-anic acid (/ometai av*iláhle as gsnerlci

4-B mg

Day's

Weeks

l-S mgrt*

GÄMnpWlIH, Girtia Inc)

200 iri^/W

Ddyi

Diyi-weCt^

l-^mg/A

Signs and symptoms of hypophosphatemia include par-esthesias, muscle weakness, myalgias, bone pain, anorexia, nausea, vomiting, red blood cell breakdown (hemo-lysis), acute respiratory failure, seizures, and coma.38,40 For mild hypophos-phatemia, patients should be encouraged to eat a high-phosphorus diet including eggs, nuts, whole grains, meat, fish, poultry, and milk products. For moderate hypophosphatemia (1-2.5 mg/dL, 0.323-0.808 mmol/L), oral supplementation of 1.5 to 2 g/day (30-60 mmol/day) is usually adequate. Diarrhea may be a dose-limiting side effect with oral phosphate replacement products. Injectable phosphate products are reserved for patients with severe hypophos-phatemia or those in the intensive care unit.41 The available agents are provided as sodium or potassium salts; however, unless concurrent hypokalemia is present, sodium phosphate is usually used. Empirically, if the serum phosphorus is 2.3 to 2.7 mg/dL (0.74-0.87 mmol/L), the corresponding IV phosphorus dose is 0.08 to 0.16 mmol/kg; for a serum phosphorus of 1.5 to 2.2 mg/dL (0.48-0.71 mmol/L), the replacement dose is 0.16 to 0.32 mmol/kg; and the dose is 0.32 to 0.64 mmol/kg when the serum phosphorus is less than 1.5 mg/dL (0.48 mmol/ L). IV phosphorus preparations are usually infused over 4 to 12 hours. Table 27-10 compares the available phosphate replacement products.

Hyperphosphatemia is defined by a serum phosphorus concentration greater than 4.5 mg/dL (1.45 mmol/L). The manifestations of hyperphosphatemia are similar to findings of hypocalcemia (see above), and include paresthesias, ECG changes (prolonged QT interval and prolonged ST segment), and metastatic calcifications. Causes of hyperphosphatemia include impaired phosphorus excretion (hypoparathyroidism or renal failure), redistribution of phosphorus to the ECF (acid-base imbalance, rhab-

domyolysis, muscle necrosis, or tumor lysis during chemotherapy), and increased

phosphorus intake (various medications). Medications that can cause hyperphosphatemia include enemas containing phosphorus (e.g., Fleet, Fleet), laxatives containing phosphate or phosphorus, oral or parenteral phosphorus supplements (e.g.,

Neutra-Phos, Ortho McNeil), vitamin D supplements, and the bisphosphonates (e.g., pamidronate, various manufacturers).

Hyperphosphatemia is generally benign and rarely needs aggressive therapy. Dietary restriction of phosphate and protein is effective for most minor elevations. Phosphate binders such as aluminum-based antacids, calcium carbonate, calcium acetate (PhosLo, Nabi), sevelamer (Renvela, Genzyme), and lanthanum carbonate (Fosrenol, Shire) may be necessary for some patients (typically those with chronic renal failure). 3 If patients exhibit findings of hypocalcemia (tetany), IV calcium should be administered empirically.

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