Epidemiology

Hypercalcemia is defined as a total serum calcium level greater than 10.5 mg/dL and is often divided into categories to describe the severity of symptoms as mild (10.5 to 11.9 mg/dL), moderate (12 to 13.9 mg/dL), and severe (>14 mg/dL).

The prevalence of hypercalcemia is approximately 0.5% to 3% in hospitalized adults.³ Hyperparathyroidism is the most common cause of hypercalcemia, and the incidence of primary hyperparathyroidism is approximately 21 cases per 100,000 person-years.⁴

The paraneoplastic syndrome hypercalcemia of malignancy is the second most common cause of hypercalcemia and occurs in approximately 10% to 30% of patients with cancer. Multiple myeloma and lung, breast, and prostate malignancies are most often associated with this disorder. It is typically seen in the end stages of disease and indicates a poor prognosis.⁵

Pathophysiology

Under normal conditions, excess calcium is excreted together with sodium in the proximal tubules of the kidneys. With hypercalcemia, dehydration caused by vomiting, poor oral intake, and osmotic diuresis results in reabsorption of sodium instead of excretion. This concurrent calcium reabsorption exacerbates the underlying hypercalcemia. PTH regulates the renal excretion of calcium. The excess production of PTH in primary hyperparathyroidism results in inappropriate calcium reabsorption. Causes of primary hyperparathyroidism include solitary adenomas (most common), ectopic adenomas in the mediastinum, diffuse hyperplasia of one or more parathyroid glands, and parathyroid carcinoma.⁶ These parathyroid abnormalities may be independent or a component of the multiple endocrine neoplasia syndromes (MEN 1 or 2a).

Bone acts as a pool of calcium that is regulated by the balance between osteoblast and osteoclast activity. Calcium is released from bone by relative overactivation of osteoclasts and is enhanced by PTH. Prolonged hyperparathyroidism results in osteopenia.

The small intestines are the location of calcium absorption from the diet. Absorption is facilitated by vitamin D. Inactive forms of vitamin D₃ are synthesized in the skin in response to exposure to sunlight; vitamin D₂ is ingested from a normal diet. Vitamins D₂ and D₃ are subsequently converted into the active form 1,25-dihydroxyvitamin D (calcitriol) by enzymatic hydroxylation first in the liver and then in the kidney. Calcitriol acts on villi of the small intestines to augment absorption of calcium and phosphorus. Calcitriol also acts on bone to increase osteoclast activity. Excessive ingestion of vitamin D supplements is a rare cause of hypercalcemia. A serum 25-hydroxyvitamin D concentration greater than 125 nmol/L (50 ng/mL) is considered to be excessive, and greater than 500 nmol/L (200 ng/mL) is potentially toxic.

In the paraneoplastic syndrome hypercalcemia of malignancy, the majority of cases of hypercalcemia arise from tumor secretion of parathyroid hormone–related protein (PTHrP), a PTH homologue that acts on tissues like PTH does. Osteolytic bone metastases and ectopic tumor production of calcitriol and PTH cause the remaining cases of hypercalcemia of malignancy.⁵

Milk-alkali syndrome is the third most common cause of hypercalcemia severe enough to result in hospitalization.⁷ The clinical definition of milk-alkali syndrome is hypercalcemia, alkalosis, and renal failure in a patient ingesting excessive amounts of calcium and an alkali. Diagnosis is based on the patient history when other causes of hypercalcemia are excluded. Over-the-counter calcium carbonate supplements are commonly used for dyspepsia and prevention of osteoporosis and are currently the most frequent cause of milk-alkali syndrome. Historically, ingestion of milk and sodium bicarbonate for the treatment of peptic ulcer disease was the most common cause of milk-alkali syndrome, but this medication regimen went out of favor with the availability of H₂ receptor antagonists and proton pump inhibitors. Serum PTH is low in these patients, indicative of no concurrent hyperparathyroidism.

Several medications rarely cause hypercalcemia. Thiazide diuretics, lithium, and the vitamin A derivatives all-trans-retinoic acid and cis-retinoic acid have been implicated. Some systemic illnesses also have the potential to cause hypercalcemia, including the granulomatous diseases sarcoidosis, leprosy, coccidiomycosis, histoplasmosis, and tuberculosis. The mechanism of hypercalcemia in these conditions is thought to be production of calcitriol by macrophages within granulomas.⁸ Additionally, rare inherited disorders such as familial hypocalciuric hypercalcemia cause hypercalcemia.⁹

Presenting Signs and Symptoms

Patients often become symptomatic from hypercalcemia at levels near 12 mg/dL, and nearly all patients with levels higher than 14 mg/dL will be symptomatic. Hypercalcemia affects a broad array of organ systems (Box 166.1).

Neurologic symptoms progress with increasing serum levels of calcium and range from mild cognitive impairment and depression to drowsiness, altered mental status, delirium, and obtundation.

Gastrointestinal symptoms include anorexia, constipation, nausea, vomiting, and paralytic ileus. Pancreatitis secondary to hypercalcemia is a well-described clinical phenomenon, but the exact mechanism of the development of this condition is still unclear. There is also an association between hypercalcemia and the development of peptic ulcer disease, in addition to a link between milk-alkali syndrome and antacid use in the treatment of this condition.

A common renal manifestation of hypercalcemia is osmotic diuresis manifested as polyuria and excessive thirst. Nephrolithiasis and nephrocalcinosis are hallmarks of hypercalcemia. In patients with primary hyperparathyroidism, up to 20% have a history of symptomatic nephrolithiasis. Case series of patients with kidney stones have demonstrated a 2% to 8% incidence of primary hyperparathyroidism.¹⁰ It is thought that excessive calciuria combined with dehydration and decreased urine output leads to stone formation.

Cardiac manifestations of hypercalcemia are generally manifested as asymptomatic electrocardiographic (ECG) changes. Shortening of the QT interval (QTc <0.4 msec) is common, and ST elevations that may mimic acute myocardial infarction have been reported^11,12 (Fig. 166.2). Symptomatic cardiac manifestations are rare and generally limited to bradydysrhythmias.

Fig. 166.2 Electrocardiographic manifestations of hypercalcemia.

Note the shortened QT interval, T-wave inversions, and ST-segment elevation.

(Courtesy Loren K. Rood, MD, Indiana University School of Medicine, Indianapolis.)

Musculoskeletal symptoms of hypercalcemia include muscle weakness, bone pain, and osteopenia.

Differential Diagnosis and Medical Decision Making

The serum calcium level is generally reported when a basic or comprehensive metabolic panel is ordered. Special consideration of hypercalcemia should be included in the evaluation of vague chief complaints such as fatigue, weakness, nausea and vomiting, abdominal pain, and altered mental status.

Discovery of significant hypercalcemia on laboratory testing should prompt a directed history for idiopathic causes of hypercalcemia, including ingestion of calcium or vitamin D supplements and use of thiazide diuretics or lithium. Evaluation for hyperparathyroidism, granulomatous diseases, and neoplasms should follow if a cause is not discovered on the history.

Treatment

Initial therapy for hypercalcemia includes correction of dehydration and facilitation of renal excretion of calcium through volume reexpansion with normal saline at a rate of 200 to 500 mL/hr. Patients with severe hypercalcemia may require several liters of fluid resuscitation. For example, in a case series of patients with severe hyperparathyroid crisis requiring parathyroidectomy, a mean of 16 ± 6 L of isotonic fluid was administered over a period of several days before surgery.⁶

Loop diuretics may be used to facilitate forced calcium excretion in urine. Evidence for the effectiveness of loop diuretics is poor, and they should be used only after normovolemia has been achieved.

An additional therapy that has been studied most extensively in patients with hypercalcemia of malignancy is the use of bisphosphonates. These medications act on osteoclasts and limit release of calcium from bone. Their maximum calcium-lowering effects do not occur until several days after administration and can last for several weeks to months.^13–15 Side effects of the bisphosphonates include hypophosphatemia, hypomagnesemia, osteonecrosis of the jaw, and postadministration acute phase reactions (fever, arthralgias, fatigue, malaise, myalgias). Table 166.1 summarizes the dosing regimens for available bisphosphonates.

A treatment of hypercalcemia that is immediately effective in lowering serum calcium is calcitonin. Calcitonin inhibits urinary reabsorption of calcium and osteoclast maturation. The most commonly available form of this medication is salmon calcitonin administered at 4 to 8 U/kg subcutaneously every 8 to 12 hours. Lowering of the serum calcium level can occur as quickly as 2 hours after administration, but the effects are generally modest (lowering calcium by up to 3.8 mg/dL)¹⁶ and short-lived. Tachyphylaxis to this treatment occurs within 2 days. Side effects of salmon calcitonin include flushing, nausea, vomiting, and abdominal cramps.

Glucocorticoids inhibit conversion of 25-hydroxyvitamin D to calcitriol, which causes a decrease in intestinal absorption of calcium and an increase in renal calcium excretion. Efficacy in lowering serum calcium has been demonstrated only in the treatment of certain types of lymphoma that secrete calcitriol, vitamin D intoxication, and the granulomatous diseases.⁸ Additionally, administration of glucocorticoids may delay tachyphylaxis to calcitonin, so they are often used in conjunction with salmon calcitonin. A common regimen for the treatment of hypercalcemia is hydrocortisone, 200 to 300 mg/day intravenously for 3 to 5 days.

An older medication for the treatment of hypercalcemia that has primarily been supplanted by use of the bisphosphonates is gallium nitrate. Gallium nitrate acts to lower serum calcium by inhibition of osteoclast activity. It is also thought to inhibit PTHrP. The typical dose is 200 mg/m²/day of gallium nitrate for 5 days by continuous infusion. The need for several days of continuous infusion is a significant drawback to the use of this medication. Because of risk for nephrotoxicity, gallium nitrate is generally indicated only when bisphosphonates are contraindicated or in refractory cases of hypercalcemia of malignancy when tumors exhibit a high level of PTHrP secretion.

An important step in the treatment of all causes of hypercalcemia is discontinuation of vitamin D and calcium-containing products. In the setting of milk-alkali syndrome, discontinuation of supplements and fluid resuscitation are often the only treatments required. Hemodialysis may be indicated for patients with severe hypercalcemia complicated by renal failure or for cases refractory to other therapies.

Follow-Up, Next Steps in Care, and Patient Education

Hospital admission is indicated for patients with symptomatic hypercalcemia, especially in the setting of altered mental status, dehydration, or acute renal failure. Definitive treatment of any underlying diseases causing hypercalcemia should be undertaken, as clinically appropriate. This may include parathyroidectomy for primary hyperparathyroidism or initiation of therapy for malignancy. Patients should be educated about the proper use of dietary supplements or antacids containing calcium and vitamin D (Table 166.2).

Epidemiology

Hypocalcemia is defined as a serum calcium level lower than 8.5 mg/dL, although symptoms of hypocalcemia typically do not occur until serum calcium is below 7.0 to 7.5 mg/dL or ionized calcium is below 2.8 mg/dL (0.7 mmol/L).¹⁷ The incidence of hypocalcemia has not been well quantified.

Pathophysiology

The most common cause of hypocalcemia is hypoparathyroidism, which is defined as inadequate release of PTH from the parathyroid glands. Inappropriate release of PTH results in poor calcium absorption from the gastrointestinal tract, excessive excretion of calcium in urine, and sequestration in bone.

The most common cause of hypoparathyroidism is neck surgery, specifically parathyroidectomy, followed by thyroidectomy and then other neck surgeries. Autoimmune destruction of the parathyroid glands also causes hypoparathyroidism. Antiparathyroid antibodies are found in more than 30% of patients with isolated hypoparathyroidism and in more than 40% of patients with hypoparathyroidism accompanied by other autoimmune diseases. Infiltration of the parathyroids as a result of sarcoidosis, Wilson disease, hemochromatosis, or amyloidosis is a rare cause of hypoparathyroidism.

Pseudohypoparathyroidism is defined as a blunted renal response to PTH and is manifested similar to hypoparathyroidism as low serum calcium and elevated phosphorus levels; PTH in this setting is normal or elevated. Several genetic pseudohypoparathyroid syndromes are associated with hypocalcemia, as well as abnormal skeletal development, dysmorphic features, and abnormal development.

Vitamin D deficiency (rickets) is rarely symptomatic in adults unless hypocalcemia develops. The majority of patients with vitamin D deficiency have osteopenia with potential for the development of osteoporosis and pathologic fractures. It is most common in elderly, hospitalized, or institutionalized persons. These patients have impaired skin production of vitamin D in response to sun exposure because of aging, a low amount of sun exposure, or dietary deficiency. Individuals with darker skin that is highly pigmented by melanin are at higher risk than lighter-skinned individuals for vitamin D deficiency secondary to relative underproduction of vitamin D in response to sun exposure. Measurement of 25-hydroxyvitamin D is considered the best measure of body vitamin D stores. Serum levels of 25-hydroxyvitamin D below 30 to 50 nmol/L (<12 to 20 ng/mL) are considered deficient.

Pancreatitis causes hypocalcemia when peripancreatic fat combines with extracellular calcium to form insoluble salts. This processes is called saponification. Other causes of hypocalcemia include sepsis, critical illness, chronic renal failure, and massive transfusion of blood anticoagulated with citrate.

DiGeorge syndrome is a rare genetic disorder caused by deletion of a portion of chromosome 22 at the location 22q11.2. Hypocalcemia is a common component of this syndrome because of parathyroid agenesis or dysgenesis. Children with this disorder may exhibit hypocalcemia shortly after birth, and many require lifelong treatment for prevention of hypocalcemia.

The electrolyte abnormalities hyperphosphatemia and hypomagnesemia also cause hypocalcemia. Drugs and toxins implicated as causes of hypocalcemia include bisphosphonates, cisplatin, ketoconazole, phenytoin, phenobarbital, proton pump inhibitors, H₂ receptor antagonists, aminoglycosides, phosphate-based enemas or laxatives, and exposure to hydrofluoric acid.

Presenting Signs and Symptoms

The primary symptoms of hypocalcemia are manifestations of calcium’s critical role in the contraction and relaxation of skeletal and smooth muscle, as well as neurotransmission (Box 166.2). Neurologic symptoms often include both sensory and motor complaints. Sensory findings include perioral and extremity paresthesias. The most common motor abnormalities are neuromuscular irritability, including muscle cramps, hyperreflexia, carpal-pedal spasms, tetany, and seizures. Smooth muscle manifestations of hypocalcemia include bronchospasm, laryngospasm, biliary and small bowel cramping, dysphagia, bladder dysfunction, and painful menses or preterm labor from uterine contractions. Laryngospasm can be life-threatening.

Two well-recognized findings on physical examination that are pathognomonic for hypocalcemia are the Chvostek and Trousseau signs. The Chvostek sign is defined as facial muscle spasm elicited by tapping the facial nerve 1 to 2 cm anterior to the tragus of the ear. This sign is neither sensitive nor specific for hypocalcemia, with 25% of healthy people having a positive sign and only 71% of hypocalcemic patients having a positive sign.¹⁷ The Trousseau sign is more reliable, with only 1% to 4% of healthy people having a positive sign and 94% of hypocalcemic patients having a positive sign. The Trousseau sign is defined as carpal and digit spasm elicited by occluding the brachial artery with a sphygmomanometer inflated to 20 to 30 mm Hg above systolic blood pressure for 3 minutes (Fig. 166.3).

Fig. 166.3 Trousseau sign in a patient with hypocalcemia and hypomagnesemia.

A 51-year-old woman had a serum calcium level of 5.4 mg/dL. A, Patient’s hand at rest. B, Patient’s hand demonstrating carpal spasm 90 seconds after inflation of the blood pressure cuff to 10 mm Hg above systolic pressure.

(From Meininger ME, Kendler JS. Images in clinical medicine. Trousseau’s sign. N Engl J Med 2000;343:1855.)

Neuropsychiatric manifestations of hypocalcemia include irritability, depression, anxiety, confusion, hallucinations, psychosis, and extrapyramidal symptoms (tremor, akathisia, slurred speech, dystonia, muscle rigidity, bradyphonia, and bradykinesia).

In addition to neuromuscular and neuropsychiatric abnormalities, cardiac conduction abnormalities and dysrhythmias may occur. The most common cardiac manifestation is QT prolongation, but bradycardia, congestive heart failure, hypotension, and triggered ventricular dysrhythmias, including torsades de pointes, may occur (Fig. 166.4).

Fig. 166.4 Prolongation of the QT interval on an electrocardiogram in a patient with hypocalcemia.

(Courtesy Richard Parks, MD, Indiana University School of Medicine, Indianapolis.)

In patients with chronic hypocalcemia, skin and ophthalmologic abnormalities may become notable. Cataracts in the lenses of the eyes, brittle nails, and coarse or dry hair and skin are typical.

Differential Diagnosis and Medical Decision Making

Hypocalcemia found on routine laboratory evaluation should prompt evaluation for hypoparathyroidism, vitamin D deficiency, renal or liver failure, hypomagnesemia, and hyperphosphatemia.

The emergency physician should consider ordering a total serum calcium or ionized calcium level in patients with a new seizure, psychosis or altered mental status, extrapyramidal symptoms, paresthesias, muscle spasms, congestive heart failure, prolonged QTc interval, or torsades de pointes.

In patients requiring massive blood transfusion, hypocalcemia should be prevented by regular assessment of calcium levels and early administration of intravenous calcium.

Calcium administration should be performed with caution in hypocalcemic patients being treated with digoxin because of the risk for precipitation of digoxin toxicity.

Treatment

The goals of therapy for hypocalcemia are to stop the uncomfortable symptoms of tetany and muscle spasm and prevent seizures, dangerous dysrhythmias, and laryngospasm. Severe, symptomatic hypocalcemia should be treated with a 10% intravenous solution of calcium gluconate or calcium chloride. The 10% solution of calcium chloride contains nearly three times the elemental calcium per milliliter as the 10% solution of calcium gluconate (Table 166.3). The dose of 10% calcium gluconate is 10 to 30 mL infused intravenously over a 10-minute period (provides 93 to 279 mg of elemental calcium). The dose of 10% calcium chloride is 10 mL infused intravenously over a 10-minute period (provides 270 mg of elemental calcium). The effects of a single bolus administration of intravenous calcium are temporary, so repeated boluses or a continuous infusion may be required in the setting of severe hypocalcemia or an ongoing process of calcium loss (pancreatitis or after parathyroidectomy). The rate of continuous infusion of calcium gluconate is 0.5 to 1.5 mg/kg/hr of elemental calcium, and it is generally supplied as 100 mL of 10% calcium gluconate in 900 mL of 5% dextrose in water (0.5 to 1.5 mL/kg/hr). Calcium chloride should be administered through a central vein. It is highly irritating to smaller peripheral veins and can cause phlebitis, and extravasation into subcutaneous tissues can result in significant local tissue necrosis.

Table 166.3 Comparison of Intravenous Solutions of Calcium for the Treatment of Hypocalcemia

Adapted from Maeda SS, Fortes EM, Oliveira UM, et al. Hypoparathyroidism and pseudohypoparathyroidism. Arq Bars Endocrinol Metab 2006;50:664–73.

Supplementation of calcium and vitamin D is the mainstay of therapy for chronic hypocalcemia. Virtually all forms of chronic hypocalcemia are associated with some degree of vitamin D deficiency. Vitamin D is available in a variety of forms. Selection of the appropriate form is based on the underlying cause of the vitamin D deficiency and the patient’s ability to appropriately hydroxylate the supplement in the liver and kidney (Table 166.4).

Oral calcium is available as a variety of salts, each with a different concentration of elemental calcium (Table 166.5). Calcium carbonate is generally preferred because it has the highest concentration of elemental calcium per tablet and thus fewer tablets are required to reach the appropriate dose of 1 to 1.5 g of elemental calcium daily.¹⁷ In the elderly, calcium citrate is preferred because it is more easily absorbed in the setting of low gastric acid.¹⁸

Table 166.5 Comparison of Calcium Salt Preparations

Adapted from Maeda SS, Fortes EM, Oliveira UM, et al. Hypoparathyroidism and pseudohypoparathyroidism. Arq Bars Endocrinol Metab 2006;50:664–73.

Follow-Up, Next Steps in Care, and Patient Education

Patients with mild, chronic, and asymptomatic hypocalcemia can follow up with their primary physician as an outpatient. Initiation of calcium and vitamin D supplementation should be considered for symptomatic individuals in discussion with the patient’s primary physician.

Patients with profound or life-threatening symptoms or any patients requiring intravenous calcium supplementation should be admitted to a monitored setting and may require intensive care unit admission. Goals of inpatient admission include serial monitoring of calcium levels, further calcium replacement, and evaluation for critical illnesses and other causes of hypocalcemia. Telemetry monitoring should be used because of the risk for precipitation of ventricular arrhythmia.

Epidemiology

Hypomagnesemia is defined as a serum magnesium level lower than 1.8 mg/dL, but most patients are not symptomatic until lower levels are reached. Two older studies demonstrated an incidence of hypomagnesemia of approximately 10% in the general hospitalized population and up to 65% in the intensive care unit patient population.^22,23 It is unclear whether this incidence has changed over time. The incidence of hypomagnesemia in patients seen in the emergency department has not been determined.

Pathophysiology

Magnesium is absorbed over the entire length of the gastrointestinal tract. Absorption is passive in the small bowel. Active transcellular absorption occurs in the colon. The direction of passive flow of magnesium can change to favor magnesium excretion into the bowel lumen in patients with conditions such as excessive diarrhea, vomiting, persistent nasogastric suction, or bulimia.^19,24 Failure to properly absorb dietary magnesium because of malabsorption syndromes such as short gut syndrome, gastric bypass, steatorrhea, celiac disease, and radiation-induced enteritis can result in chronic hypomagnesemia.

Failure of renal magnesium absorption occurs in settings of osmotic diuresis as a result of hypercalcemia, hyperglycemia, and mannitol administration. Renal tubular, glomerular, and interstitial diseases may also result in an inability to properly reabsorb magnesium.

Hypomagnesemia may be triggered by acute pancreatitis secondary to saponification of fatty acids. A baseline poor dietary intake of magnesium from chronic alcohol abuse that precipitates pancreatitis may also contribute to hypomagnesemia in these patients.

Other causes of hypomagnesemia include acidosis, chronic alcoholism, non–magnesium-containing laxative abuse, and several drugs, including diuretics, aminoglycosides, amphotericin B, cisplatin, and cyclosporine.

Presenting Signs and Symptoms

Hypomagnesemia is highly correlated with abnormalities in other electrolytes. Hypokalemia is common because magnesium is necessary for proper function of the sodium-potassium adenosine triphosphatase (Na⁺,K⁺-ATPase) pump, which maintains an appropriate transcellular potassium gradient. Hypomagnesemia impairs secretion of PTH, causes renal and bone resistance to PTH, and causes intestinal resistance to vitamin D, thereby resulting in hypocalcemia.¹⁹

Similar to hypocalcemia, hypomagnesemia results in significant neuromuscular hyperexcitability. The Chvostek and Trousseau signs may be present.

Magnesium has been demonstrated to be helpful in the treatment of dangerous arrhythmias, especially torsades de pointes and atrial fibrillation, thus suggesting that hypomagnesemia plays a role in the development of these arrhythmias. ECG changes associated with hypomagnesemia include prolongation of the PR and QTc intervals and the development of U waves (Fig. 166.5).

Fig. 166.5 A, Prolongation of the QT interval on an electrocardiogram in a patient with hypomagnesemia. B, Deterioration of the same patient’s rhythm to torsades de pointes, which was corrected with intravenous magnesium.

(Courtesy Loren K. Rood, MD, Indiana University School of Medicine, Indianapolis.)

Differential Diagnosis and Medical Decision Making

Magnesium levels should be checked and normalized in patients with known or suspected hypocalcemia or hypokalemia and in patients with weakness or sensory-motor complaints. Assessment of the underlying cause of hypomagnesemia, especially in the setting of gastrointestinal losses, is necessary.

Treatment

Treatment of hypomagnesemia is slow intravenous infusion of 2 to 4 g of a 50% magnesium sulfate solution. It may be repeated as necessary, to a maximum dose of 8 g/day. This maximum dose is often exceeded in patients being treated with continuous infusions of magnesium sulfate for preeclampsia or tocolysis, so continuous monitoring for signs of hypermagnesemia are indicated in these patients.

Follow-Up, Next Steps in Care, and Patient Education

Hospital admission is indicated for patients with life-threatening complications of hypomagnesemia, including seizures and cardiac arrhythmias. Mild, chronic hypomagnesemia can be treated on an outpatient basis with supplementation of magnesium salts. Dietary or lifestyle changes, including cessation of alcohol abuse, may be necessary to completely rectify the hypomagnesemia.

Epidemiology

Hypermagnesemia is defined as a serum magnesium level higher than 2.5 mg/dL. Hypermagnesemia is rare because of efficient renal excretion of excessive magnesium. In 1990 a published series of more than 1000 hospitalized adult patients demonstrated a 5.7% prevalence of hypermagnesemia in this population.²⁵ There are multiple case reports in the emergency medicine literature of hypermagnesemia caused by iatrogenic and accidental overdoses.²⁶

Pathophysiology

In the setting of iatrogenic or accidental overdose of magnesium, renal excretion of magnesium can be overwhelmed. The imbalance of absorption over excretion is worsened in the setting of acquired or chronic renal insufficiency, especially in patients with a glomerular filtration rate lower than 30 mL/min. Symptomatic hypermagnesemia is seen most often in the setting of iatrogenic administration of intravenous magnesium or after an overdose of magnesium-containing supplements or enemas. Concomitant use of anticholinergic or opiate medications that slow gastrointestinal motility can increase the risk for toxicity from magnesium-containing medications.²⁷

Magnesium acts as a nonspecific calcium channel blocker. This property results in cardiac conduction abnormalities and hypotension in patients with acute elevations in magnesium.

Presenting Signs and Symptoms

The symptoms of hypermagnesemia progress in a dose-related fashion (Table 166.7). Early signs of hypermagnesemia include headache, nausea, vomiting, flushing, and hypotension as a result of peripheral vasodilation. Reflexes diminish and are eventually lost. Mental status worsens from somnolence to coma. Muscle weakness can progress to include the muscles of respiration and result in ventilatory failure and the need for endotracheal intubation and mechanical ventilation. At higher magnesium levels, cardiac complications begin to develop, with progression from bradycardia to atrioventricular block, intraventricular conduction block, complete heart block, or asystole.

Table 166.7 Symptoms of Hypermagnesemia

Adapted from Birrer RB, Shallash AH, Totten V. Hypermagnesemia-induced fatality following Epson salt gargles. J Emerg Med 2002;22:185–8.

Differential Diagnosis and Medical Decision Making

Hypermagnesemia should be included in the differential diagnosis of patients with altered mental status, cardiac arrhythmias, hypotension, and shock. A directed history of use of over-the-counter antacids, laxatives, and enemas should be elicited when hypermagnesemia is suspected or found on laboratory analysis.

Treatment

The mainstay of treatment of hypermagnesemia is cessation of the use of any magnesium-containing medications. Fluid resuscitation with isotonic saline followed by diuretic therapy to encourage renal clearance of excessive magnesium is indicated. In patients with significant cardiac complications of hypermagnesemia, 10 to 20 mL of 10% calcium gluconate should be administered and repeated every 5 to 10 minutes as needed. Intravenous calcium administration antagonizes the natural calcium channel–blocking properties of magnesium. Hemodialysis may be required in the setting of hypermagnesemia and renal failure.

Follow-Up, Next Steps in Care, and Patient Education

Hospital admission to a monitored setting or intensive care unit is indicated in the setting of severely elevated magnesium levels, especially with levels that place the patient at risk for hypotension, cardiac conduction abnormalities, or ventilatory failure.

Patients should be educated about the appropriate use of magnesium-containing antacids and laxatives and be made aware of the possibility of overdose when these medications are not used appropriately.

Epidemiology

Hypophosphatemia is rare in the general population, occurs in only 2% to 3% of hospitalized patients,^31,32 but is much more common in the setting of critical illness, in which the incidence of phosphorus levels lower than 2.5 mg/dL ranges from 24% to 100%, depending on the intensive care unit population studied.³³

Pathophysiology

There are three predominant mechanisms of hypophosphatemia.³³ Acute hypophosphatemia occurs in the setting of forces that drive phosphate excessively from the extracellular space into the intracellular space. Respiratory alkalosis and treatment of diabetic ketoacidosis with insulin are two common examples of this form of hypophosphatemia. Refeeding syndrome, in which severely malnourished patients are fed a diet high in carbohydrate, is a rare cause of hypophosphatemia but may be encountered in the treatment of patients with severe anorexia nervosa.

Increased urinary excretion of phosphorus (as seen in primary and secondary hyperparathyroidism) and decreased intestinal absorption of phosphorus are the two other mechanisms of hypophosphatemia. Decreased dietary intake of phosphorus, excessive use of phosphate-binding antacids, vomiting, nasogastric suctioning, diarrhea, vitamin D deficiency, and malabsorption are all causes of decreased intestinal absorption of phosphorus. Chronic alcoholism can result in both dietary deficiency and excessive renal excretion of phosphorus.

Presenting Signs and Symptoms

The symptoms of hypophosphatemia worsen with falling serum levels. Patients with mild hypophosphatemia, or serum levels in the range of 2.0 to 2.5 mg/dL, are often asymptomatic. With moderate hypophosphatemia in the range of 1.0 to 2.0 mg/dL, patients may experience myalgias, muscle weakness, and anorexia. Severe hypophosphatemia, defined as a serum phosphorus level lower than 1.0 mg/dL, results in paresthesias, tremor, confusion, decreased deep tendon reflexes, cardiac arrhythmias and impaired cardiac contractility, impaired respiratory muscle function, seizures, and coma.

Rhabdomyolysis can occur in the setting of severe hypophosphatemia secondary to an inability to maintain muscle membrane integrity as a result of ATP deficiency.

Differential Diagnosis and Medical Decision Making

When hypophosphatemia is discovered, causes of respiratory alkalosis should be considered, including hyperventilation from salicylate toxicity, anxiety, pain, alcohol withdrawal, and chronic obstructive pulmonary disease.

Hypophosphatemia should be excluded in patients with myalgias, weakness, and rhabdomyolysis. Phosphorus levels should be monitored in patients being treated for diabetic ketoacidosis.

Treatment

Patients with severe phosphorus deficiency (serum phosphorus <1 mg/dL) should receive intravenous replacement in the form of either sodium phosphate or potassium phosphate. Potassium phosphate is preferred in patients with concomitant hypokalemia. Multiple studies have examined the safety of various doses and rates of administration of intravenous phosphorus supplementation. Doses up to 45 mmol and rates of 20 mmol/hr have been demonstrated to be safe when administered through a central venous catheter.^31,33 The typical dose recommended for adults is 0.08 to 0.16 mmol/kg (2.5 to 5 mg/kg) administered over a period of 2 to 6 hours.³⁴ Intravenous administration of phosphate-containing supplements can precipitate hypocalcemia, as well as hyperkalemia when potassium phosphate is used.

Mild hypophosphatemia (serum phosphorus level of 1 to 2 mg/dL) may be treated with oral phosphate-containing supplements at a dose of up to 1000 to 2000 mg daily, divided three or four times per day. A combination sodium phosphate and potassium phosphate tablet is available (K-Phos Neutral) that contains 250 mg of phosphorus, 298 mg (13 mEq) of sodium, and 45 mg of potassium (1.1 mEq). Cow’s milk is a rich dietary source of phosphorus that contains approximately 1 mg of phosphorus per 1 mL of milk.³⁵

Follow-Up, Next Steps in Care, and Patient Education

Patients with severe hypophosphatemia are often critically ill and require admission for management of their underlying illnesses. Patients with severe, symptomatic hypophosphatemia should be admitted for replacement therapy and monitoring of electrolytes.

Epidemiology

Hyperphosphatemia is defined as a serum phosphorus level higher than 4.5 mg/dL, with severe hyperphosphatemia being defined as serum levels higher than 14 mg/dL. The most common cause of hyperphosphatemia is chronic renal failure requiring hemodialysis. Nearly 90% of these patients are managed with phosphorus-binding therapy and diets low in phosphorus to limit hyperphosphatemia.³⁶

Pathophysiology

In patients with chronic renal failure, gastrointestinal absorption of phosphorus continues, but renal excretion ceases. Hemodialysis removes approximately 800 to 1000 mg of phosphorus per session,³⁰ which is less than the typical dietary intake of phosphorus—a mainstay of treatment of hyperphosphatemia is limiting dietary intake and absorption of phosphorus. Excessive phosphorus combines with calcium to form salts that are deposited in the soft tissues of the body. Deposition in the soft tissues of the heart, kidneys, and vasculature has the potential to cause abnormalities in cardiac electrical conduction and cardiac muscle relaxation and contraction, as well as renal disease, coronary artery disease, and peripheral vascular disease. Some evidence indicates that calcium phosphate salt deposition increases mortality in patients undergoing hemodialysis.³⁶

Causes of acute elevations in phosphorus include hemolysis, tumor lysis syndrome, and rhabdomyolysis. All three conditions result in rapid breakdown of cellular membranes, which allows stores of intracellular phosphate to quickly be released into the extracellular space. Unless concomitant renal insufficiency is present or ongoing cellular destruction is occurring, the hyperphosphatemia in these conditions is self-limited because renal excretion soon exceeds extracellular phosphate shifting when supportive care is given.

Vitamin D toxicity and overuse of phosphate-containing antacids or enemas have been reported as causes of acute hyperphosphatemia resulting from excessive gastrointestinal absorption. An additional cause of chronic hyperphosphatemia is hypoparathyroidism. In the setting of impaired PTH secretion, renal excretion of phosphorus is decreased.

Presenting Signs and Symptoms

The symptoms of hyperphosphatemia are generally the consequence of associated renal failure and hypocalcemia and include altered mental status, seizures, dysrhythmias, prolongation of the QTc interval, muscle weakness, and neuromuscular excitability (see Box 166.2).

Differential Diagnosis and Medical Decision Making

Acute hyperphosphatemia should prompt evaluation for acute renal failure, rhabdomyolysis, tumor lysis syndrome, and hemolysis. Calcium, magnesium, and potassium levels should be assessed in patients with hyperphosphatemia because many of these electrolyte abnormalities occur simultaneously.

Treatment

In the setting of acute hyperphosphatemia it is necessary to treat the underlying cause. This includes limiting further cell breakdown as much as possible in patients with hemolysis, tumor lysis syndrome, and rhabdomyolysis. Increasing renal excretion of phosphorus with fluid resuscitation, alkalinization of urine with sodium bicarbonate, and diuretic therapy are also indicated.

In the setting of chronic hyperphosphatemia secondary to hypoparathyroidism or chronic renal failure, the mainstays of therapy are to reduce the dietary intake and gastrointestinal absorption of phosphorus.

Phosphate-binding salts are frequently used in the treatment of hyperphosphatemia in patients with renal failure.³⁶ The cheapest and best-tolerated phosphate binders are calcium carbonate and calcium acetate. These medications may increase deposition of calcium phosphate salt in soft tissues, but considerable debate exists about the cost-effectiveness and side effect profile of alternative phosphate binders. Gastrointestinal side effects of nausea and diarrhea are common. Magnesium hydroxide, magnesium carbonate, sevelamer hydrochloride, sevelamer carbonate, and lanthanum are alternative phosphate-binding salts used for the treatment of hyperphosphatemia in patients with renal failure.

Follow-Up, Next Steps in Care, and Patient Education

Patients with severe, acute hyperphosphatemia, especially in the setting of acute renal failure or symptomatic hypocalcemia, require admission for supportive care. Many patients with chronic hyperphosphatemia are asymptomatic and require only outpatient follow-up for dietary modifications or adjustment of phosphate-binding salt regimens.