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  1. Calcium acts as a key signaling element for many cellular functions and is the most abundant electrolyte in the body. Normal values of total serum calcium range from 8.5 to 10.5 mg/dL (4.5-5.5 mEq/L). However, because calcium is bound to protein (~40%), the appropriate range of total serum calcium that can provide for adequate ionized calcium is dependent on the total serum calcium and the amount of serum protein (particularly albumin). The ionized calcium provides a better functional assessment, with normal values ranging from 4 to 5 mg/dL (2.1-2.5 mEq/L or 1.05-1.25 mmol/L). Direct measurement of ionized calcium is commonly available and is superior to “corrected” calcium values based on albumin levels. Ionized calcium can be affected by the pH of the serum, with acidemia leading to higher ionized calcium and alkalemia to lower ionized calcium. Modulators of calcium homeostasis include parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D, which increase calcium levels, and calcitonin, which decreases calcium levels.
    1. Hypercalcemia (see Chapter 26): A total serum calcium of greater than 10.5 mg/dL (5.5 mEq/L or 2.6 mmol/L) or ionized calcium of greater than 5.0 mg/dL (2.5 mEq/L or 1.25 mmol/L)
      1. Causes of hypercalcemia
        1. Primary hyperparathyroidism
        2. Immobilization
        3. Malignancy (bone destruction from metastases or hormone secretion)
        4. Granulomatous diseases (tuberculosis, sarcoidosis), secondary to increased 1,25-dihydroxyvitamin D production by the granulomatous tissue
        5. Thyrotoxicosis
        6. Primary bone reabsorption abnormalities (Paget disease)
        7. Adrenal insufficiency
        8. Pheochromocytoma
        9. Milk-alkali syndrome: high intake of calcium (>5 g/d)
        10. Drugs (thiazides, vitamin D, lithium, estrogens)
      2. Diagnosis
        1. PTH levels: low in malignancy-associated hypercalcemia and high in primary, secondary, and tertiary hyperparathyroidism
        2. 1,25-dihydroxyvitamin D levels: elevated in granulomatous disease
        3. PTH-related protein: elevated in malignancy-associated hypercalcemia (breast, lung, thyroid, renal cells)
        4. Protein electrophoresis: monoclonal band associated with myeloma
        5. Thyroid-stimulating hormone (TSH)
        6. Chest radiographs: Evaluate for malignancy and granulomatous disease.
      3. Manifestations: Hypercalcemia will affect multiple organ systems, including neurologic, cardiovascular, renal, GI, and musculoskeletal. The patient may exhibit muscle weakness, lethargy, and, possibly, coma. ECG abnormalities include bradycardia, shortened QT interval, increased PR and QRS intervals, and atrioventricular block. Polyuria, nephrolithiasis, and nephrogenic DI are common. GI manifestations include nausea/vomiting, constipation, and pancreatitis.
      4. Treatment is described in detail in Chapter 26. Here, we summarize the main considerations. Treatment should be initiated if neurologic symptoms are present, total serum calcium is greater than 12 to 13 mg/dL, or calcium/phosphate product is greater than 75.
        1. First, begin immediate hydration with NS to restore volume status and decrease serum calcium concentration by dilution.
        2. After establishing euvolemia, a loop diuretic can be added to NS with the goal of generating a urine output of 3 to 5 mL/kg/h.
        3. Other electrolytes should be repleted.
        4. Hemodialysis, if the abovementioned therapy is ineffective
        5. The use of pamidronate, calcitonin, and glucocorticoids is described in detail in Chapter 26. Calcium channel blockers can also be used to treat the cardiotoxic effects of hypercalcemia.
    2. Hypocalcemia (see Chapter 26): an ionized calcium of less than 4 mg/dL (2.1 mEq/L or 1.05 mmol/L)
      1. Causes of hypocalcemia
        1. Sequestration of calcium can be caused by hyperphosphatemia (from renal failure), pancreatitis, intravascular citrate (from PRBCs), and alkalemia.
        2. PTH deficiency can be caused by surgical excision of the parathyroid gland, autoimmune parathyroid disease, amyloid infiltration of the parathyroid gland, severe hypermagnesemia, hypomagnesemia, HIV infection, and hemochromatosis.
        3. PTH resistance is due to congenital abnormality or secondary to hypomagnesemia.
        4. Vitamin D deficiency is caused by malabsorption, poor nutritional intake, liver disease, anticonvulsants (phenytoin), inadequate sunlight, and renal failure.
        5. Inappropriate calcium deposition can be due to formation of complex with phosphorus in hyperphosphatemic states (rhabdomyolysis), acute pancreatitis, and post-parathyroidectomy.
        6. Sepsis and toxic shock syndrome
      2. Manifestations of hypocalcemia include generalized excitable membrane irritability leading to paresthesias and progressing to tetany and seizures. The classic physical examination findings include Trousseau sign (spasm of the upper extremity muscles that causes flexion of the wrist and thumb with extension of the fingers and can be elicited by occluding the circulation to the arm) and Chvostek sign (contraction of the ipsilateral facial muscles elicited by tapping over the facial nerve at the jaw). ECG changes include prolonged QT and heart block. Respiratory manifestations include apnea, bronchospasm, and laryngeal spasm (typically seen after thyroidectomy or parathyroidectomy surgery). Anxiety and depression may also be seen as neurologic manifestations of hypocalcemia.
      3. Diagnosis
        1. Confirm true hypocalcemia by checking ionized calcium and pH.
        2. Rule out hypomagnesemia.
        3. Check PTH level; if low or normal, hypoparathyroidism may be involved; if high, check for phosphorus level. A low phosphorus level suggests pancreatitis or vitamin D deficiency, whereas a high phosphorus level suggests rhabdomyolysis or renal failure.
      4. Therapy for hypocalcemia: Infusion of calcium at 4 mg/kg of elemental calcium with either 10% calcium gluconate (93 mg of calcium/10 mL) or 10% calcium chloride (272 mg of calcium/10 mL). A bolus should be followed by an infusion because the bolus will increase the ionized form of calcium for 1 to 2 hours. To avoid precipitation of calcium salts, intravenous (IV) calcium solutions should not be mixed with IV bicarbonate solutions. Calcium chloride is caustic to peripheral veins and should be given via central venous access if possible. Suspected vitamin D or PTH deficiency is treated with calcitriol (0.25 µg, up to 1.5 µg po once a day). Oral calcium repletion with at least 1 g of elemental calcium a day should be given along with vitamin D therapy.
  2. Phosphorus exists mainly as a free ion in the body. Approximately 0.8 to 1 g of phosphorus is excreted in the urine per day. Phosphorus excretion is affected by PTH (which inhibits proximal and distal nephron phosphorus reabsorption), vitamin D, high dietary phosphorus intake, cortisol, and growth hormone.
    1. Hypophosphatemia occurs in 10% to 15% of patients who have been hospitalized.
      1. Causes
        1. Gastrointestinal: malnutrition, malabsorption, vitamin D deficiency, diarrhea, and use of aluminum-containing antacids
        2. Renal losses: primary hyperparathyroidism, renal transplantation, ECF expansion, diuretics (acetazolamide), Fanconi syndrome, post-obstructive uropathy and post-acute tubular necrosis (ATN), glycosuria, DKA
        3. Redistribution: alkalosis, post-alcohol withdrawal, parenteral hyperalimentation, burns, and continuous venovenous hemofiltration
      2. Manifestations usually occur when phosphorus is less than 1.0 mg/dL.
        1. Neurologic: metabolic encephalopathy
        2. Muscular: myopathy, respiratory failure, cardiomyopathy
        3. Hematologic: hemolysis, white blood cell dysfunction
      3. Diagnosis
        1. Urinary phosphorus less than 100 mg/d suggests GI losses.
        2. Urinary phosphorus greater than 100 mg/d suggests renal wasting.
        3. Elevated serum calcium suggests hyperparathyroidism.
        4. Elevated PTH suggests primary or secondary hyperparathyroidism or calcipenic rickets.
      4. Treatment
        1. Increase oral intake to 1000 mg/d.
        2. Elemental phosphorus: 450 mg per 1000 kcal of hyperalimentation
        3. Dose of IV phosphorus should not exceed 2 mg/kg (0.15 mmol/kg) of elemental phosphorus.
    2. Hyperphosphatemia
      1. Causes
        1. Renal: decreased glomerular filtration rate (GFR), increased tubular reabsorption, hypoparathyroidism, pseudohypoparathyroidism, acromegaly, thyrotoxicosis
        2. Endogenous: tumor lysis, rhabdomyolysis
        3. Exogenous: vitamin D administration, phosphate enemas
      2. Manifestations are related to hypocalcemia due to calcium phosphate deposition and decreased renal production of 1,25-dihydroxyvitamin D.
      3. Treatment
        1. Phosphate binders to reduce GI absorption
        2. Volume expansion and dextrose 10% in water with insulin may reduce acutely elevated phosphorus levels.
        3. Hemodialysis and peritoneal dialysis
  3. Magnesium: Serum magnesium is maintained between 1.8 and 2.3 mg/dL (1.7-2.1 mEq/L); 15% is protein bound.
    1. Hypermagnesemia is rare in patients with normal renal function. It is defined as greater than 2.5 mg/dL.
      1. Causes
        1. Acute and chronic renal failure
        2. Magnesium administration for toxemia of pregnancy, magnesium- containing antacids and laxatives
        3. Hypothyroidism
        4. Lithium toxicity
      2. Manifestations
        1. Cardiac dysrhythmias and hypotension
        2. Decreased neuromuscular transmission
        3. CNS dysfunction: confusion, lethargy
        4. Respiratory depression
      3. Treatment
        1. IV calcium
        2. Hemodialysis to remove magnesium in renal failure
    2. Hypomagnesemia is defined as serum magnesium less than 1.8 mg/dL.
      1. Causes
        1. Gastrointestinal
          1. Decreased intake (chronic alcoholism)
          2. Starvation
          3. Magnesium-free enteral feedings
          4. Decreased GI intake because of nasogastric suction and malabsorption
        2. Renal losses
          1. Diuretic therapy
          2. Post-obstructive diuresis
          3. Recovery (polyuric phase) from ATN
          4. DKA versus hypercalcemia
          5. Primary hyperaldosteronism
          6. Bartter syndrome and Gitelman syndrome
          7. Aminoglycoside, cisplatin, and cyclosporine nephrotoxicity
      2. Manifestations
        1. Hypokalemia and hypocalcemia; hypokalemia is the result of excess urine losses, which can only be corrected with magnesium repletion.
        2. ECG changes mimic hypokalemia.
        3. Digoxin toxicity is magnified by hypomagnesemia.
        4. Neuromuscular fasciculations with Chvostek and Trousseau signs may be present.
      3. Treatment for hypomagnesemia should be initiated when ECG changes and/or signs of tetany are present.
        1. Intravenous: with MgSO4, 6 g in 1 L of 5% dextrose in water over 6 hours
        2. Oral: with magnesium oxide, 250 to 500 mg 4 times a day