Download Calcium.. - SLR EM Education

166 Calcium, Magnesium, and Phosphorus
Katrina A. Leone
FACTS AND FORMULAS
KEY POINTS
• Regulation of calcium, magnesium, and phosphorus is
interrelated, and abnormalities in one are highly
correlated with other electrolyte abnormalities.
• Severely depressed mental status and precipitation of
arrhythmias are the most dangerous consequences of
severe abnormalities in calcium, magnesium, or
phosphorus.
• Proper correction of electrolyte deficiencies requires
knowledge of the various oral and intravenous
electrolyte preparations available.
Normal serum calcium
level
8.5-10.5 mg/dL (2.1-2.6 mmol/dL)
Normal ionized
calcium level
4.5-5.6 mg/dL (1.1-1.4 mmol/L)
Normal serum
magnesium level
1.8-2.5 mg/dL (0.74-0.94 mmol/L)
Normal serum
phosphorus level
2.5-4.5 mg/dL (0.81-1.45 mmol/L)
Total serum calcium
level corrected for
albumin:
For every 1 g/dL in albumin,
serum calcium drops 0.8 mg/dL
Corrected calcium
(mg/dL)
Measured calcium (mg/dL) +
0.8[4.4 − albumin (g/dL)]
Calcium
calcium, phosphorus, parathyroid hormone (PTH), and
1,25-dihydroxyvitamin D (calcitriol)1,2 (Fig. 166.1).
Approximately 99% of total body calcium is located in bone
as the calcium phosphate salt hydroxyapatite. Of the remaining total body calcium, 45% is bound to albumin; 10% is
complexed with circulating ions such as bicarbonate, phosphate, citrate, or sulfate1; and the remaining 45% is found in
the free, ionized form. The normal range for serum calcium
is 8.5 to 10.5 mg/dL, with some variability among different
laboratories. The normal range of ionized (unbound) calcium
is 4.5 to 5.6 mg/dL, but this is often reported in the international units (SI units) of mmol/L, with the normal range being
1.1 to 1.4 mmol/L. This ionized fraction is responsible for the
physiologic actions of calcium and is not dependent on
albumin levels. The total serum calcium level can be corrected
for the amount of serum albumin (see the “Facts and Formulas” box), but such correction can be unreliable, so an ionized
calcium level should be obtained whenever true hypercalcemia or hypocalcemia is a concern.
The plasma concentration of calcium is tightly maintained
within the normal range by a feedback-regulated endocrine
system that balances interactions among the small intestines,
kidneys, bones, parathyroid glands, thyroid gland, and bloodstream. The key regulatory molecules in this system include
HYPERCALCEMIA
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
1405
SECTION XVI
METABOLIC AND ENDOCRINE DISORDERS
Low serum calcium
or
High serum phosphorus
Parathyroid
Diet
Sun
exposure
D2
D3
D3
PTH
Bone
Small
intestines
Increased
calcium +
phosphorus
release
Kidneys
1,25(OH) 2D
Increased
calcium +
phosphorus
absorption
Increased
serum
calcium
+
23(OH) D
Liver
Increased
calcium
reabsoption,
phosphorus
excretion
+
25(OH) D
hydroxylation
Decreased
serum
phosphorus
Fig. 166.1 Calcium homeostasis. Parathyroid hormone (PTH) is released from the parathyroid glands in response to hypocalcemia and
hyperphosphatemia. PTH acts on bone, the small intestines, and the kidneys to effect a rise in serum calcium and a net decrease in serum
phosphorus. Hydroxylation of inactive forms of vitamin D occurs in the liver and kidneys. 1,25(OH)2D facilitates intestinal absorption of
calcium and phosphorus. 1,25(OH)2D, 1,25-Dihydroxyvitamin D; 25(OH) D, 25-hydroxyvitamin D; D2, vitamin D2; D3, vitamin D3.
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
1406
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
CHAPTER 166
BOX 166.1 Signs and Symptoms
of Hypercalcemia
Neurologic
Fatigue
Weakness
Delirium
Coma
Gastrointestinal
Anorexia
Nausea and vomiting
Constipation or ileus
Peptic ulcers
Pancreatitis
Renal
Osmotic diuresis
Nephrolithiasis
Nephrocalcinosis
Cardiac
QT-interval shortening
ST-segment elevation
Bradydysrhythmias
Musculoskeletal
Muscle weakness
Bone pain
Osteopenia
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-transretinoic 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
Calcium, Magnesium, and Phosphorus
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 reported11,12 (Fig. 166.2). Symptomatic
cardiac manifestations are rare and generally limited to
bradydysrhythmias.
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 calciumlowering 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
1407
SECTION XVI
METABOLIC AND ENDOCRINE DISORDERS
I
↓aVR
↓V1
↓V4
II
↓aVL
↓V2
↓V5
III
↓aVF
↓V3
↓V6
II
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.)
Table 166.1 Bisphosphonates Available in the United States for the Treatment of Hypercalcemia of Malignancy
MEDIAN TIME TO RELAPSE
OF HYPERCALCEMIA
DOSE*
INFUSION TIME
Pamidronate
60 or 90 mg
2-4 hr
17 days
Zoledronic acid
4 or 8 mg
15 min
30-40 days
Adapted from Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled
analysis of two randomized, controlled clinical trials. J Clin Oncol 2001;19:558-67.
*Higher doses are reserved for patients with severely elevated calcium levels.
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
1408
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 calciumcontaining 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
CHAPTER 166
Calcium, Magnesium, and Phosphorus
Table 166.2 Recommended Daily Dietary Intake of Vitamins and Minerals by Age and Sex
4-8
1-3
Vitamin D (mcg)
F
9-13
M
F
14-18
M
F
19-30
M
F
31-50
M
F
51+
M
F
M
5
5
5
5
5
5
5
5
5
5
5
10
10
500
800
800
1300
1300
1300
1300
1000
1000
1000
1000
1200
1200
Magnesium (mg)
80
130
130
240
240
360
410
310
400
320
420
320
420
Phosphorus (mg)
460
500
500
1250
1250
1250
1250
700
700
700
700
700
700
Calcium (mg)
From U.S. Department of Agriculture Center for Nutrition Policy and Promotion. Report of the Dietary Guidelines Advisory Committee on the Dietary
Guidelines for Americans, 2010. Available at http://www.dietaryguidelines.gov. Accessed 1/14/2011.
F, Female; M, male.
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).
HYPOCALCEMIA
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
1409
SECTION XVI
METABOLIC AND ENDOCRINE DISORDERS
A
B
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.)
BOX 166.2 Symptoms of Hypocalcemia,
Hypomagnesemia, and Hyperphosphatemia
Neuromuscular
Paresthesias
Cramps
Carpal-pedal spasms
Tetany
Seizures
Cardiovascular
QT-interval prolongation
Bradycardia
Congestive heart failure
Hypotension
Dysrhythmias (torsades de pointes)
Pulmonary
Laryngospasm
Bronchospasm
Psychiatric
Irritability
Depression
Altered mental status
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
1410
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).
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).
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.
CHAPTER 166
Calcium, Magnesium, and Phosphorus
I
aVR
V1
V4
II
aVL
V2
V5
III
aVF
V3
V6
V1
II
V5
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.)
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.
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).
Table 166.3 Comparison of Intravenous Solutions
of Calcium for the Treatment of Hypocalcemia
SOLUTION
10% Calcium chloride
(1 g/10 mL)
10% Calcium
gluconate
(1 g/10 mL)
ELEMENTAL
CALCIUM
(IN 10 mL)
270 mg
93 mg
DOSE
10 mL IV over
10-min period
10-30 mL IV
over 10-min
period
Adapted from Maeda SS, Fortes EM, Oliveira UM, et al.
Hypoparathyroidism and pseudohypoparathyroidism. Arq Bars
Endocrinol Metab 2006;50:664-73.
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
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.
1411
SECTION XVI
METABOLIC AND ENDOCRINE DISORDERS
Table 166.4 Comparison of Vitamin D Supplement Preparations
HEPATIC
HYDROXYLATION
REQUIRED
RENAL
HYDROXYLATION
REQUIRED
Ergocalciferol (vitamin D2)
+
Cholecalciferol (vitamin D3)
SUPPLEMENT
DOSAGE FORMS
NOTES
+
50,000 IU
+
+
400, 1000, 2000, 5000 IU
Considered
equivalent
Calcidiol (25-hydroxyvitamin D)
−
+
Not available
Calcitriol
(1,25-dihydroxyvitamin D)
−
−
0.25, 0.5 mcg
Available PO and
IV, expensive
The biologic activity of 40 IU is equivalent to 1 mcg.
Adapted from Maeda SS, Fortes EM, Oliveira UM, et al. Hypoparathyroidism and pseudohypoparathyroidism. Arq Bars Endocrinol Metab 2006;50:664-73;
and Tohme JF, Bilezikian JP. Hypocalcemic emergencies. Endocrinol Metab Clin North Am 1993;22:363-75.
Table 166.5 Comparison of Calcium Salt Preparations
SUPPLEMENT
ELEMENTAL
CALCIUM CONTENT
AMOUNT OF SALT REQUIRED TO OBTAIN THE RECOMMENDED
DAILY DOSE FOR ADULTS (1 g ELEMENTAL CALCIUM/DAY)
Calcium carbonate
40%
2.5 g
Calcium phosphate
38%
2.6 g
Calcium chloride
27%
3.7 g
Calcium citrate
21%
4.8 g
Calcium lactate
13%
7.7 g
9%
11.1 g
Calcium gluconate
Adapted from Maeda SS, Fortes EM, Oliveira UM, et al. Hypoparathyroidism and pseudohypoparathyroidism. Arq Bars Endocrinol Metab 2006;50:664-73.
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.
Magnesium
Approximately 50% of total body magnesium is found in bone
as a component of hydroxyapatite, similar to calcium. The
remaining magnesium is located primarily intracellularly.
Only 1% of total body magnesium is found in the extracellular
space, with this amount further divided into protein-bound
(30%) and ionized fractions.19
1412
The balance between gastrointestinal absorption and renal
excretion determines the serum magnesium level, with bone
acting as a buffer to increase serum magnesium when levels
are low. Neither gastrointestinal absorption nor renal excretion of magnesium is hormonally regulated. Circulating PTH
regulates bone metabolism. Because serum magnesium levels
influence release of PTH from the parathyroid glands, magnesium has an effect on serum calcium and phosphorus levels.
The kidneys have the ability to reabsorb all but 0.5% of the
filtered magnesium in the setting of hypomagnesemia and
excrete up to 80% in the setting of hypermagnesemia.20 The
normal serum range of magnesium is 1.8 to 2.5 mg/dL (0.74
to 0.94 mmol/L). No ionized magnesium laboratory test is
available.
The recommended daily intake of elemental magnesium for
adults is 320 mg for women and 420 mg for men. Dietary
sources of magnesium include fish, nuts, cereals, and green
vegetables. A variety of magnesium salt formulations are used
therapeutically as laxatives and magnesium supplements
(Table 166.6).
Magnesium acts as a cofactor for an extensive number of
intracellular enzymatic reactions and is necessary for protein
and DNA synthesis, as well as for adenosine triphosphate
(ATP) function and glucose metabolism.21 It is also critical for
neuromuscular conduction and muscle contraction.
CHAPTER 166
Calcium, Magnesium, and Phosphorus
Table 166.6 Common Magnesium-Containing Preparations
SUPPLEMENT
ELEMENTAL MAGNESIUM
CONTENT (%)
AMOUNT OF ELEMENTAL MAGNESIUM
IN COMMON PREPARATIONS
Magnesium oxide
61
242 mg in 400-mg tablet
Magnesium hydroxide (milk of magnesia)
42
167 mg in 400 mg/5 mL oral suspension
Magnesium citrate
16
48 mg in 290 mg/5 mL oral solution
Magnesium gluconate
5
27 mg in 500-mg tablet
Magnesium chloride
12
64 mg in 535-mg tablet
Magnesium sulfate solution
10
500 mg in 10 mL of a 50% solution (5 mg MgSO4/10 mL)
Magnesium sulfate
Epson salts
10
98 mg in 1 g of salts
Magnesium lactate
12
10 mg in 84-mg tablet
Magnesium aspartate
10
122 mg in 1230-mg tablet
Adapted from Guerrera MP, Volpe SL, Mao JJ. Therapeutic uses of magnesium. Am Fam Physician 2009;80:157-62.
HYPOMAGNESEMIA
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).
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.
1413
SECTION XVI
METABOLIC AND ENDOCRINE DISORDERS
I
↓aVR
↓V1
↓V4
II
↓aVL
↓V2
↓V5
III
↓aVF
↓V3
↓V6
II
A
B
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.)
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 lifethreatening 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.
HYPERMAGNESEMIA
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.
EPIDEMIOLOGY
PRESENTING SIGNS AND SYMPTOMS
Hypermagnesemia is defined as a serum magnesium level
higher than 2.5 mg/dL. Hypermagnesemia is rare because of
The symptoms of hypermagnesemia progress in a dose-related
fashion (Table 166.7). Early signs of hypermagnesemia
1414
CHAPTER 166
Table 166.7 Symptoms of Hypermagnesemia
MAGNESIUM LEVEL
SYMPTOMS
5-8 mg/dL
Nausea, vomiting, flushing,
hyporeflexia
9-12 mg/dL
Somnolence, areflexia, hypotension,
bradycardia, prolongation of the
QRS, PR, and QT intervals
>15 mg/dL
Respiratory depression, complete
heart block, paralysis, coma
>20 mg/dL
Asystole, death
Adapted from Birrer RB, Shallash AH, Totten V. Hypermagnesemiainduced fatality following Epson salt gargles. J Emerg Med
2002;22:185-8.
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.
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
Calcium, Magnesium, and Phosphorus
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.
Phosphorus
Eighty percent to 85% of total body phosphorus is contained
in bone, complexed with calcium and magnesium as hydroxyapatite. Less than 1% of total body phosphorus is found extracellularly in plasma; the remaining phosphorus is located
intracellularly. Phosphorus is the most abundant intracellular
anion.
Phosphorus exists as organic and inorganic forms—it is the
inorganic forms that are measured in the laboratory determination of serum phosphorus. Within the range of typical body
pH, inorganic phosphorus exists as a balance between the
phosphate anions H2PO4− and HPO4−2. At neutral pH the ratio
of H2PO4− to HPO4−2 is 1 : 4. The normal serum range of phosphorus is 2.5 to 4.5 mg/dL (0.81 to 1.45 mmol/L).28
Adequate phosphorus levels are important for multiple lifesustaining processes. Phosphorus is a key component of ATP,
which is required for the generation of energy to carry out
cellular processes. It is a part of the phospholipids that make
up cell membranes, as well as DNA and RNA. Phosphorus is
also necessary for 2,3-diphosphoglycerate in red blood cells,
which facilitates release of oxygen from hemoglobin.
The balance between gastrointestinal absorption, bone
anabolism and catabolism, and renal excretion determines
serum phosphorus levels. Passive absorption of phosphorus
from the diet occurs in the small intestines. Vitamin
D–dependent active absorption also occurs and is responsible
for approximately 30% of phosphorus absorption.29 Foods
rich in phosphorus include animal proteins, milk, eggs and
multiple food preservatives.30
Excretion of phosphorus occurs in the kidneys. Serum
phosphorus is freely filtered by the glomeruli, with 80% to
90% being reabsorbed though an Na/PO4 cotransporter in the
proximal tubules. PTH enhances the excretion of phosphorus
by inhibiting this transporter. When PTH is released from the
parathyroid gland, it acts on bone to release calcium and
phosphorus. It also stimulates the kidney to increase production of 1,25-dihydroxyvitamin D, which results in increased
gastrointestinal absorption of calcium and phosphorus. Both
these mechanisms result in efficient increases in serum
calcium, but the increase in serum phosphorus is modest.
When combined with the increased excretion of phosphorus
by the kidneys in response to PTH, the net effect of a rise in
PTH is a decrease in serum phosphorus and an increase in
serum calcium (see Fig. 166.1).
1415
SECTION XVI
METABOLIC AND ENDOCRINE DISORDERS
HYPOPHOSPHATEMIA
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.
1416
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.
HYPERPHOSPHATEMIA
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
CHAPTER 166
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 selflimited 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.
Calcium, Magnesium, and Phosphorus
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. Gastro­
intestinal 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.
SUGGESTED READINGS
Amanzadeh J, Reily Jr RF. Hypophosphatemia: an evidence-based approach to its
clinical consequences and management. Nat Clin Pract Nephrol 2006;2:136-48.
Moe SM. Disorders involving calcium, phosphorus, and magnesium. Prim Care
2008;35:215-37, v-vi.
Pellitteri PK. Evaluation of hypercalcemia in relation to hyperparathyroidism.
Otolaryngol Clin North Am 2010;43:389-97.
Phitayakorn R, McHenry CR. Hyperparathyroid crisis: use of bisphosphonates as a
bridge to parathyroidectomy. J Am Coll Surg 2008;206:1106-15.
Tonelli M, Pannu N, Manns B. Oral phosphate binders in patients with kidney failure.
N Engl J Med 2010;362:1312-24.
REFERENCES
TREATMENT
References can be found
www.expertconsult.com.
on
Expert
Consult
@
In the setting of acute hyperphosphatemia it is necessary to
treat the underlying cause. This includes limiting further cell
1417
CHAPTER 166
REFERENCES
1. Kleeman CR, Massry SG, Coburn JW. The clinical physiology of calcium
homeostasis, parathyroid hormone, and calcitonin. I. Calif Med
1971;114(3):16-43.
2. Kleeman CR, Massry SG, Coburn JW. The clinical physiology of calcium
homeostasis, parathyroid hormone, and calcitonin. II. Calif Med
1971;114(4):19-30.
3. Frolich A. Prevalence of hypercalcemia in normal and hospitalized populations.
Dan Med Bull 1998;45:436-9.
4. Wermers RA, Khosla S, Atkinson EJ, et al. Incidence of primary
hyperparathyroidism in Rochester, Minnesota, 1993-2001: an update on the
changing epidemiology of the disease. J Bone Miner Res 2006;21:171-7.
5. McMahan J, Linneman T. A case of resistant hypercalcemia of malignancy with a
proposed treatment algorithm. Ann Pharmacother 2009;43:1532-8.
6. Phitayakorn R, McHenry CR. Hyperparathyroid crisis: use of bisphosphonates as
a bridge to parathyroidectomy. J Am Coll Surg 2008;206:1106-15.
7. Ulett K, Wells B, Centor R. Hypercalcemia and acute renal failure in milk-alkali
syndrome: a case report. J Hosp Med 2010;5:E18-20.
8. Ariyan CE, Sosa JA. Assessment and management of patients with abnormal
calcium. Crit Care Med 2004;32:S146-54.
9. Pellitteri PK. Evaluation of hypercalcemia in relation to hyperparathyroidism.
Otolaryngol Clin North Am 2010;43:389-97.
10. Berger AD, Wu W, Eisner BH, et al. Patients with primary hyperparathyroidism—
why do some form stones? J Urol 2009;181:2141-5.
11. Donovan J, Jackson M. Hypercalcemia mimicking STEMI on electrocardiography.
Case Report Med 2010;2010:563-72.
12. Turhan S, Kilickap M, Kilinc S. ST segment elevation mimicking acute
myocardial infarction in hypercalcemia. Heart 2005;91:999.
13. Mundy GR, Wilkinson R, Heath DA. Comparative study of available medical
therapy for hypercalcemia of malignancy. Am J Med 1983;74:421-32.
14. Ralston SH, Gardner MD, Dryburg FJ. Comparison of aminohydroxypropylidene
diphosphonate, mithramycin, and corticosteroids/calcitonin in treatment of
cancer-associated hypercalcemia. Lancet 1985;2:907-10.
15. Ralston SH, Gallacher SJ, Dryburg FJ. Treatment of severe hypercalcemia with
mithracmycin and aminohydroxypropylidene bisphosphonate. Lancet 1988;2:277.
16. Heath DA. The emergency management of disorders of calcium and magnesium.
Clin Endocrinol Metab 1980;9:487-502.
17. Maeda SS, Fortes EM, Oliveira UM, et al. Hypoparathyroidism and
pseudohypoparathyroidism. Arq Bars Endocrinol Metab 2006;50:664-73.
Calcium, Magnesium, and Phosphorus
18. Tohme JF, Bilezikian JP. Hypocalcemic emergencies. Endocrinol Metab Clin
North Am 1993;22:363-75.
19. Rude RK. Magnesium metabolism and deficiency. Endocrinol Metab Clin North
Am 1993;22:377-95.
20. Nadieri ASA, Reilly Jr RF. Hereditary etiologies of hypomagnesemia. Nat Clin
Pract Nephrol 2008;4:80-9.
21. Moe SM. Disorders involving calcium, phosphorus, and magnesium. Prim Care
2008;35:215-37, v-vi.
22. Wong ET, Rude RK, Singer FR, et al. A high prevalence of hypomagnesemia and
hypermagnesemia in hospitalized patients. Am J Clin Pathol 1983;79:348-52.
23. Ryzen E, Wagers PW, Singer FR, et al. Magnesium deficiency in a medical ICU
population. Crit Care Med 1985;13:19-21.
24. Alexander RT, Hoenderop JG, Bindels RJ. Molecular determinant of magnesium
homeostasis: insights from human disease. J Am Soc Nephrol 2008;19:1451-8.
25. Whang R, Ryder KW. Frequency of hypomagnesemia and hypermagnesemia.
Requested vs. routine. JAMA 1990;263:3063-4.
26. Vissers RJ, Purssell R. Iatrogenic magnesium overdose: two case reports. J Emerg
Med 1996;14:187-91.
27. Birrer RB, Shallash AH, Totten V. Hypermagnesemia-induced fatality following
Epson salt gargles. J Emerg Med 2002;22:185-8.
28. Hodgson SF, Hurley DL. Acquired hypophosphatemia. Endocrinol Metab Clin
North Am 1993;22:363-75.
29. Bergwitz C, Juppner H. Regulation of phosphate homeostasis by PTH, vitamin D,
and FGF23. Annu Rev Med 2010;61:91-104.
30. Uribarri J. Phosphorus homeostasis in normal health and in chronic kidney
disease patients with special emphasis on dietary phosphorus intake. Semin Dial
2007;20:295-301.
31. Brunelli SM, Goldfarb S. Hypophosphatemia: clinical consequences and
management. J Am Soc Nephrol 2007;18:1999-2003.
32. Shiber JR, Mattu A. Serum phosphate abnormalities in the emergency
department. J Emerg Med 2002;23:395-400.
33. Geerse DA, Bindels AJ, Kuiper MA, et al. Treatment of hypophosphatemia in the
intensive care unit: a review. Crit Care 2010;14:R147.
34. Amanzadeh J, Reily Jr RF. Hypophosphatemia: an evidence-based approach to its
clinical consequences and management. Nat Clin Pract Nephrol 2006;2:136-48.
35. Gaasbeek A, Meinder E. Hypophosphatemia: an update on its etiology and
treatment. Am J Med 2005;118:1094-101.
36. Tonelli M, Pannu N, Manns B. Oral phosphate binders in patients with kidney
failure. N Engl J Med 2010;362:1312-24.
1417.e1