Management
Prevention
Managing Hypercalcemia
Mild Hypercalcemia
Moderate to Severe Hypercalcemia
Pharmacologic Inhibition of Osteoclastic Bone Resorption
Bisphosphonates
Calcitonin
Plicamycin
Gallium nitrate
Other Therapeutics for Hypercalcemia
Glucocorticoids
Phosphate
Dialysis
Prostaglandin synthesis Inhibitors
Cisplatin
Patient and Family Education
Supportive Care
Psychosocial Management
Management of hypercalcemia
Prognosis
Prevention
Individuals at risk of developing hypercalcemia may be the first to recognize
symptoms such as fatigue. Patients should be advised about the ways in which
hypercalcemia most frequently manifests itself and should also be given
guidelines for seeking professional intervention. Preventive measures include
ensuring adequate fluid intake of 3 to 4 L (100–140 fl oz per day if not
contraindicated) and salt intake, nausea and vomiting control, encouraging
patient mobility, attention to febrile episodes, and cautious use or
elimination of drugs that may complicate management. This includes drugs that
inhibit urinary calcium excretion or decrease renal blood flow, as well as
medications that contain calcium, vitamin D, vitamin A, or other retinoids.[1]
Even though the gut has a role in normal calcium homeostasis, absorption is
usually diminished in individuals with hypercalcemia, making dietary calcium
restriction unnecessary.
Managing Hypercalcemia
Symptomatic treatment of hypercalcemia focuses first on correcting dehydration
and enhancing renal calcium excretion, followed by specific hypocalcemic
treatment with agents that inhibit bone resorption (e.g., calcitonin,
bisphosphonates, gallium nitrate, and plicamycin).[2,3] Definitive treatment
is that which effectively treats the malignant disease underlying
hypercalcemia.[4] At one time, hypercalcemia was treated with aggressive
intravenous hydration using isotonic saline followed by the administration of a
diuretic. This volume expansion and natriuresis was performed to increase renal
blood flow and enhance calcium excretion. This approach is not very effective
in correcting hypercalcemia and can lead to complications of fluid overload.
Intravenous fluid should be administered to correct water loss associated with
calciuresis and dehydration due to vomiting. Administration of diuretics
should be restricted to balancing urine output in patients who have been
adequately rehydrated.[1]
The magnitude of hypercalcemia and the severity of symptoms typically form the
basis for determining whether treatment is indicated. Immediate aggressive
hypocalcemic treatment is warranted in patients with a corrected total serum
calcium level higher than 14 mg/dL (>7 mEq/L or 3.5 mmol/L). In patients with a total
corrected serum calcium concentration between 12 and 14 mg/dL (6–7 mEq/L or
3.0–3.5 mmol/L), clinical manifestations should guide the type of therapy and
the urgency with which it is implemented.[2] Treatment response is indicated
by resolution of symptoms attributable to hypercalcemia and by diminishing
serum calcium concentrations and urinary calcium and hydroxyproline excretion.
Aggressive treatment is not generally indicated in patients with mild
hypercalcemia (corrected total serum calcium level lower than 12 mg/dL [<6 mEq/L or 3.0
mmol/L]). Clear treatment decisions are problematic for patients with mild
hypercalcemia and coexistent central nervous system symptoms, especially for
younger patients in whom hypercalcemia is generally better tolerated. It is
very important to evaluate other causes for altered central nervous system
function before attributing them solely to hypercalcemia.[2]
Treatment can provide marked improvement of distressing symptoms. Polyuria,
polydipsia, central nervous system symptoms, nausea, vomiting, and constipation
are more likely to be managed successfully than are anorexia, malaise, and
fatigue. Pain control may be improved for some patients who achieve
normocalcemia.[5] Effective calcium-lowering therapy usually improves
symptoms, enhances the quality of life, and may allow patients to be managed in
a subacute, ambulatory, or home care setting.
After normocalcemia is achieved, serum calcium should be monitored serially,
with the frequency determined by anticipated duration of response to any
particular hypocalcemic regimen.
Mild Hypercalcemia
Mild hypercalcemia is defined as corrected total serum calcium level lower than 12 mg/dL (<6 mEq/L or 3.0 mmol/L).
Hydration followed by observation is a treatment option. This option should be
considered for asymptomatic patients who are about to be treated for tumors
that are likely to respond to antineoplastic treatment (e.g., lymphoma, breast
cancer, ovarian cancer, head and neck carcinoma, and multiple myeloma).[6]
In symptomatic patients or when tumor response to therapy is expected to occur
slowly, therapy for hypercalcemia should be implemented to manage symptoms and
stabilize patients’ metabolic states. Additional ancillary interventions
should be directed toward controlling nausea and vomiting, encouraging mobility,
noting febrile episodes, and the minimal use of sedating medications.[6]
Moderate to Severe Hypercalcemia
Moderate to severe hypercalcemia is defined as corrected total serum calcium equal to 12 to 14 mg/dL (6–7 mEq/L or 3.0–3.5
mmol/L).
Rehydration is the essential first step in treating moderate or severe
hypercalcemia. Although fewer than 30% of patients achieve normocalcemia with
hydration alone, replenishing extracellular fluid, restoring intravascular
volume, and saline diuresis are fundamental to initial therapy. Adequate
rehydration may require 3,000 to 6,000 mL of 0.9% sodium chloride for injection
(normal saline) within the first 24 hours to restore fluid volume. Restoring
normal extracellular fluid volume will increase daily urinary calcium excretion
by 100 to 300 mg. Clinical improvement in mental status and nausea and
vomiting is usually apparent within 24 hours for most patients; however,
rehydration is a temporizing intervention. If definitive cytoreductive
therapies (surgery, radiation, or chemotherapy) are not forthcoming,
hypocalcemic agents must be used to achieve long-term control.
Thiazide diuretics increase renal tubular calcium absorption and may exacerbate
hypercalcemia. Thus, thiazide diuretics are contraindicated in hypercalcemia
patients. Loop diuretics (e.g., furosemide, bumetanide, and ethacrynic acid)
induce hypercalciuria by inhibiting calcium reabsorption in the ascending limb
of the loop of Henle, but they should not be administered until fluid volume is
restored. Otherwise, loop diuretics can exacerbate fluid loss, further
reducing calcium clearance. Because sodium and calcium clearance are closely
linked during osmotic diuresis, loop diuretics will depress the proximal
tubular resorptive mechanisms for calcium, increasing calcium excretion to 400
to 800 mg per day.
Moderate doses of furosemide (20–40 mg every 12 hours) increase saline-induced
urinary calcium excretion and are useful in preventing or managing fluid
overload in adequately rehydrated patients. Aggressive treatment with
furosemide (80–100 mg every 2–4 hours) is problematic because it requires
concurrent administration of large volumes of saline to prevent intravascular
dehydration.[7] This, in turn, requires intensive hemodynamic monitoring (to
avoid volume overload and cardiac decompensation) and frequent serial measurements of
urinary volume and electrolytes (to prevent life-threatening
hypophosphatemia, hypokalemia, and hypomagnesemia).[6,8]
Pharmacologic Inhibition of Osteoclastic Bone Resorption
Described below are therapies that can inhibit osteoclastic bone resorption.
The most widely used modality for this purpose is a bisphosphonate (such as
pamidronate). The use of other agents such as calcitonin, mithramycin, or
gallium nitrate is less common.
Bisphosphonates
Bisphosphonates are one of the most effective pharmacologic alternatives for
controlling hypercalcemia. They bind to hydroxyapatite in calcified bone,
rendering it resistant to hydrolytic dissolution by phosphatases, thereby
inhibiting both normal and abnormal bone resorption.[9] Bisphosphonate
treatment reduces the number of osteoclasts in sites undergoing active bone
resorption and may prevent osteoclast expansion by inhibiting differentiation
from their monocyte-macrophage precursors.[10] Bisphosphonates have variable
effects on other aspects of bone remodeling, such as new bone formation and
mineralization. For example, etidronate at clinically relevant dosages
(300–1,600 mg/day) inhibits new bone formation and mineralization.[11] With
prolonged etidronate use, osteomalacia and pathologic fractures may
occur.[12] In contrast, clodronate, pamidronate, and alendronate are 10,
100, and 1,000 times more potent inhibitors of bone resorption than etidronate
and are clinically useful at dosages that are less likely to adversely affect
new bone formation and mineralization.[13-16] Many
bisphosphonates may be useful in treating hypercalcemia of malignancy. In the
United States, etidronate and pamidronate are the only bisphosphonates approved
for treating hypercalcemia.
In a randomized double-blind study comparing pamidronate with etidronate for
the treatment of cancer-related hypercalcemia, pamidronate (60 mg intravenous [IV] single dose over 24 hours) has been demonstrated to be more
effective with respect to serum calcium reduction and duration of hypocalcemic
response than etidronate (7.5 mg/kg of body weight per day administered over 2
hours as a daily IV infusion for 3 consecutive days).[17] This finding has
led to the diminished use of etidronate.[1]
In treating moderate hypercalcemia (corrected serum calcium <13.5 mg/dL, <6.75
mEq/L, or <3.37 mmol/L), pamidronate 60 to 90 mg IV is administered over 2 to 24 hours.[18] Onset of pamidronate’s effect is apparent within 3 to
4 days, with maximal effect within 7 to 10 days after commencing treatment.
The effect may persist for 7 to 30 days.[19] It is recommended that a
minimum of 7 days elapse before re-treatment with pamidronate to
assess full response to the initial dose.[18] Adverse effects include
transient low-grade temperature elevations (1°C–2°C) that typically occur
within 24 to 36 hours after administration and persist for up to 2 days in up
to 20% of patients. Pamidronate has also been used successfully in children, with similar side effects.[20] Other bisphosphonates (except clodronate) may also produce
transient temperature elevations; the incidence of temperature elevation,
nausea, anorexia, dyspepsia, and vomiting may be increased by rapid
administration.[21,22] New-onset hypophosphatemia and hypomagnesemia may
occur; pre-existing abnormalities in the same electrolytes may be exacerbated
by treatment. Serum calcium may fall below the normal range, and hypocalcemia
(typically asymptomatic) may result. Renal failure has only been reported
after rapid etidronate and clodronate injection, but rapid administration
should be avoided with all bisphosphonates.[23] Intravenous pamidronate
administration has been associated with acute-phase responses, including
transiently decreased peripheral lymphocyte counts. Local reactions
(thrombophlebitis, erythema, and pain) at the infusion site have been
reported.[21]
The use of subcutaneous (SC) administration of
clodronate has been explored. Initial experience suggested that clodronate was well tolerated
subcutaneously; however, aminobisphosphonates such as pamidronate resulted in
local irritation.[24] In a subsequent study, 37 inpatients with terminal
cancer received 45 clodronate infusions.[25] Clodronate, 1,500 mg in 1 L
of normal saline, was administered via a 23-gauge, ¾-inch butterfly needle
into the SC space. All the infusions were completed, and none required
discontinuation due to discomfort. The authors concluded that their results
suggested that SC clodronate is an effective treatment for
hypercalcemia of malignancy and is associated with minimal toxicity. This
technique has advantages in the care of terminally ill patients at home and may
avoid the need for hospital admission and/or IV administration. In
addition, SC administration in the hospital setting has advantages
for patients for whom an IV site may be problematic.
Calcitonin and plicamycin have a more rapid hypocalcemic effect than
bisphosphonates; however, pamidronate has several advantages over
nonbisphosphonate therapies. In comparison with plicamycin, response rates are
greater among patients treated with pamidronate.[26] Pamidronate more
frequently reduces serum calcium concentrations to normocalcemic ranges than
either calcitonin or plicamycin.[26,27] In addition, pamidronate’s
hypocalcemic effect is dose related and sustained after repeated
administration, and it generally persists longer than the effects produced
by either calcitonin or plicamycin therapies.[19] Pamidronate lacks the renal,
hepatic, and platelet toxic effects associated with plicamycin.
Calcitonin
Calcitonin is a peptide hormone secreted by specialized cells in the thyroid
and parathyroid. Its synthesis and secretion normally increase in response to
high concentrations of serum-ionized calcium. Calcitonin opposes physiologic
effects of parathyroid hormone on bone and renal tubular calcium resorption;
however, it is not known whether calcitonin has a significant role in calcium
homeostasis. Nevertheless, calcitonin rapidly inhibits calcium and phosphorous
resorption from bone and decreases renal calcium reabsorption. Calcitonin
derived from salmon is much more potent and is longer acting
than the human hormone. The initial dose schedule is 4 IU/kg of body weight per SC dose or intramuscular (IM) dose every 12 hours. Dose and
schedule may be escalated after 1 or 2 days to 8 IU/kg every 12 hours, and
finally to 8 IU/kg every 6 hours if the response to lower doses is
unsatisfactory. Unfortunately, tachyphylaxis commonly occurs. With repeated
use, calcitonin’s beneficial hypocalcemic effect wanes, even at the upper
recommended limits of dose and schedule, so that its calcium-lowering effect
lasts for only a few days. In patients who are responsive to calcitonin, its
combination with bisphosphonates may hasten the onset and duration of a
hypocalcemic response caused by calcitonin’s rapid (within 2–4 hours) onset of
action.[28,29]
Calcitonin is usually well tolerated; adverse effects include mild nausea,
transient cramping abdominal pain, and cutaneous flushing. Calcitonin is most
useful within the first 24 to 36 hours of treatment of severe hypercalcemia and
should be used in conjunction with more potent but slower-acting agents.
Plicamycin
Plicamycin (also referred to as mithramycin) is an inhibitor of osteoclast RNA
synthesis. It has been shown to inhibit bone resorption in vitro and is
clinically effective in the presence or absence of bone metastases. Onset of
response occurs within 12 hours of a single IV dose of 25 to 30 μg/kg
of body weight given as a short infusion for 30 minutes or longer. Maximum
response, however, does not occur until approximately 48 hours after
administration and may persist for 3 to 7 days or more after administration.
Repeated doses may be given to maintain plicamycin’s hypocalcemic effect but
should not be given more frequently than every 48 hours to determine
the maximum calcium-lowering effect produced by previous doses.[30] Multiple
doses may control hypercalcemia for several weeks, but rebound hypercalcemia
usually occurs without definitive treatment against the underlying
malignancy.[31] Although single-dose treatment of hypercalcemia is generally
well tolerated with few adverse effects,[32] dysfibrinogenemia [33] and
nephrotoxicity [34] have been reported after single doses (20–25 μg/kg). Rapid
IV administration is associated with nausea and vomiting.[31] High
and repeated doses predispose the patient to thrombocytopenia, a qualitative
platelet dysfunction that may be associated with a bleeding diathesis,
transient increases in hepatic transaminases, nephrotoxicity (decreased
creatinine clearance, increased serum creatinine and blood urea nitrogen, potassium wasting,
and proteinuria), hypophosphatemia, a flulike syndrome, dermatologic
reactions, and stomatitis.[31,34-39]
Gallium nitrate
Gallium nitrate was developed as an antineoplastic agent that was
coincidentally found to produce a hypocalcemic effect. Gallium nitrate
interferes with an adenosine triphosphatase–dependent proton pump in the
membrane of osteoclasts. This impairs osteoclast acidification and the
dissolution of the underlying bone matrix.[1] Gallium nitrate has been shown
to be superior to etidronate in the percentage of patients who achieve
normocalcemia and in the duration of normocalcemia.[40] Drawbacks to its use
include a continuous 5-day IV infusion schedule (200 mg/m2
of body surface area per day) [6] and the potential for nephrotoxicity, particularly
when it is used concurrently with other potentially nephrotoxic drugs (e.g.,
aminoglycosides and amphotericin B).[1]
Gallium nitrate has also been given by daily SC injection to prevent
bone resorption and maintain bone mass in patients with multiple myeloma.[41]
Other Therapeutics for Hypercalcemia
Glucocorticoids
Glucocorticoids have efficacy as hypocalcemic agents primarily in
steroid-responsive tumors (e.g., lymphomas and myeloma) and in patients whose
hypercalcemia is associated with increased vitamin D synthesis or intake
(sarcoidosis and hypervitaminosis D).[42,43] Glucocorticoids increase urinary
calcium excretion and inhibit vitamin D–mediated gastrointestinal calcium
absorption. Response, however, is typically slow; 1 to 2 weeks may elapse
before serum calcium concentrations decrease. Oral hydrocortisone (100–300 mg)
or its glucocorticoid equivalent may be given daily; however, complications of
long-term steroid use limit its usefulness even in responsive patients.
Phosphate
Phosphate offers a minimally effective chronic oral treatment for mild to
moderate hypercalcemia. It is most useful after successful initial reduction
of serum calcium with other agents and should probably be reserved for patients
who are both hypercalcemic and hypophosphatemic. The usual treatment is 250 to
375 mg per dose given 4 times daily (1–1.5 g of elemental phosphorus per day) to
minimize the potential for developing hyperphosphatemia.[44] Supranormal
phosphate administration results in decreased renal calcium clearance and
presumably decreases serum calcium concentrations by precipitating calcium into
bone and soft tissues.[45,46] Extraskeletal precipitation of calcium in vital
organs may have adverse consequences and is especially significant after
intravenous administration.[6,47,48] IV administration of phosphate
produces a rapid decline in serum calcium concentrations but is rarely used
because there are safer and more effective antiresorptive agents for
life-threatening hypercalcemia (calcitonin and plicamycin). Hypotension,
oliguria, left ventricular failure, and sudden death can occur as a result of
rapid IV administration. Contraindications for phosphate include
normophosphatemia, hyperphosphatemia, and renal insufficiency. Oral phosphate
should be given at the lowest dose possible to maintain serum phosphorous
concentrations lower than 4 mg/dL 1 to 2 hours after administration.
The use of phosphates is limited by individual patient tolerance and toxicity;
25% to 50% of patients cannot tolerate oral phosphates.[8] Oral
phosphate–induced diarrhea may be initially advantageous in patients who have
experienced constipation secondary to hypercalcemia; it is the predominant and
dose-limiting adverse effect for oral therapy and frequently prevents dosage
escalation of more than 2 g of neutral phosphate per day.[6]
Dialysis
Dialysis is an option for hypercalcemia that is complicated by renal failure.
Peritoneal dialysis with calcium-free dialysate fluid can remove 200 to 2,000
mg of calcium in 24 to 48 hours and decrease the serum calcium concentration by
3 to 12 mg/dL (1.5–6 mEq/L or 0.7–3 mmol/L). Ultrafiltrable calcium clearance
may exceed that of urea with calcium-free dialysate exchanges of 2 L each every
30 minutes.[49] Hemodialysis is equally effective.[50,51] Because large
quantities of phosphate are lost during dialysis and phosphate loss aggravates
hypercalcemia, serum inorganic phosphate should be measured after each dialysis
session, and phosphate should be added to the dialysate during the next fluid
exchange or to the patient’s diet.[52] It is recommended, however, that
phosphate replacement should be limited to restoring serum inorganic phosphate
concentrations to normal rather than supranormal.[44]
Prostaglandin synthesis Inhibitors
Prostaglandin synthesis inhibitors such as the nonsteroidal anti-inflammatory
drugs may have some efficacy in the management of cancer-induced hypercalcemia.
The E-series prostaglandins mediate bone resorption. Despite experimental
evidence, however, aspirin and other nonsteroidal drugs have demonstrated only
modest clinical response rates in controlling hypercalcemia. For patients who
are unresponsive to or unable to tolerate other agents, aspirin may be given to
produce a serum salicylate concentration equal to 20 to 30 mg/dL, or 25 mg
indomethacin may be given orally every 6 hours.[53-56]
Cisplatin
Serum calcium was normalized for a median of 34 days (range, 4–115) in 9 of
13 patients with various solid tumors given IV cisplatin at 100 mg/m2
of body surface area over 24 hours. Patients were re-treated as
frequently as every 7 days if necessary to maintain serum calcium
concentrations lower than 11.5 mg/dL (<5.75 mEq/L or 2.87 mmol/L). Four of seven
patients responded to repeated treatment. Responders achieved a statistically
significant difference in serum calcium levels from baseline on the tenth day
after treatment, which continued thereafter. Serial tumor measurements
revealed that the hypocalcemic response did not correlate with tumor shrinkage;
there was no detectable antitumor response in any measurable or evaluable
disease.[57]
Future pharmacologic management is likely to combine osteoclastic inhibitors
with cytotoxic or endocrine therapy.[9]
Patient and Family Education
Hypercalcemia compromises the patient’s quality of life and can be
life-threatening if not promptly recognized and treated. Individuals at risk
and their caregivers should be made aware that hypercalcemia is a possible
complication. Patients and their significant others should be advised about
the types of symptoms that may occur with hypercalcemia, preventive measures,
exacerbating factors, and when to seek medical assistance.[58] They should be
taught measures to diminish the symptoms of hypercalcemia such as maintaining
mobility and ensuring adequate hydration.
Supportive Care
Despite encouraging developments in pharmacologic management, the prognostic
implications related to hypercalcemia remain relatively grim. Only patients
for whom effective anticancer therapy is possible can be expected to experience
a longer survival.
The adverse effects of therapy need to be prevented or recognized and managed.
Fluid overload and electrolyte imbalance can occur during initial therapy.
Serum sodium, potassium, calcium, phosphate, and magnesium concentrations may
be markedly decreased. Electrolyte levels should be monitored at least daily,
and clinical signs and symptoms should be assessed at least every 4 hours when
hydration or specific hypocalcemic drug treatments are being implemented.
The management of symptoms of hypercalcemia is crucial. Preventing accidental
or self-inflicted injury as a consequence of the patient’s altered mental
status is a priority during acute management. Until serum calcium decreases,
additional pharmacologic interventions may be necessary to control nausea,
vomiting, and constipation.
Any acute severe exacerbation or development of new bone pain should be
evaluated for the presence of a pathological fracture. Many health care
facilities institute fracture precautions for patients with metastatic disease
to the bone. These precautions include gentle handling when moving or
transferring patients and fall-prevention strategies. Maximum mobility and
weight-bearing exercises are desirable.
Supportive care in terminal stages typically consists of comfort measures for
patients and their caregivers. Changes in mentation and behavior may be
especially distressing to family members.
Psychosocial Management
Supportive management of delirium, agitation, or changes in mental status is
implemented in patients with hypercalcemia. Primary treatment of
hypercalcemia and/or its underlying etiology eventually leads to the
resolution of changes in mental status in most of these patients. Some patients
present with clinically significant and distressing changes in mental status,
agitation, or delirium that warrants management or control. (Refer to the PDQ
summary on Cognitive Disorders and Delirium 1 for more information.) Clinical experience supports the
use of neuroleptic medications such as haloperidol (0.5–5.0 mg IV or by mouth 2–4 times a day) alone or in
combination with benzodiazepines (e.g., 0.5–2.0 mg of lorazepam IV or by mouth 2–4 times a day) for the control of agitation
and confusion. This enhances patient and family comfort and allows for easier
institution of primary therapies. The use of benzodiazepines in these
situations should be reserved for instances in which sedation (and not
improvement in mental status) is the primary goal of the intervention.
The relationship between mental status and serum calcium levels is variable.
Some patients will not manifest improvement in mental status until days to a
week or more after serum calcium levels are in the normal range; others will
display improvement before laboratory values catch up.
Many times, lethargy is a presenting symptom of hypercalcemia. Lethargic
patients are often mistakenly believed by family (and sometimes by staff)
to be depressed before the actual etiology of the mental-status changes becomes
known. The differential diagnosis is generally straightforward in that many of
these patients will lack the cognitive or ideational symptoms of a mood
disorder (hopelessness, helplessness, anhedonia, guilt, worthlessness, or
thoughts of suicide) and instead will appear mainly lethargic and apathetic; formal testing of mental status is likely to reveal cognitive deficits. This
is an important distinction to be made, as the introduction of antidepressant
drugs during an organic confusional episode can worsen confusion.
Management of hypercalcemia
- Correct dehydration due to calciuresis and vomiting with IV
hydration using isotonic saline.
- Prevent or manage fluid overload with a diuretic such as furosemide, 20 mg to 40
mg every 12 hours.
- Treat hypercalcemia with one of the following agents:
- pamidronate, 60 to 90 mg IV over 2 to 24 hours.
- calcitonin, 4 IU/kg SC or IM every 12 hours.
- plicamycin, 25 to 30 μg/kg IV over 30 minutes.
- gallium nitrate, 200 mg/m2 per day IV over 24 hours for 5
consecutive days.
- Provide patient and family education:
- Signs and symptoms of hypercalcemia to report to the health care provider:
- Lethargy.
- Fatigue.
-
Confusion.
-
Loss of appetite.
-
Nausea/vomiting.
-
Constipation.
-
Excessive thirst.
- Preventive measures:
- Maintain mobility.
- Ensure adequate hydration.
- Provide supportive care:
- Protect from injury.
- Prevent fractures.
- Manage related symptoms (e.g., nausea, vomiting, and constipation).
- Manage mental-status changes:
- Haloperidol, 0.5 to 5 mg IV or by mouth 2 to 4 times a day for agitation or confusion.
- Benzodiazepines such as lorazepam, 0.5 to 2 mg every 4 to 6 hours as needed for
sedation.
Prognosis
Hypercalcemia generally develops as a late complication of malignancy; its
appearance has grave prognostic significance. It remains unclear, however,
whether death is associated with hypercalcemic crisis (uncontrolled or
recurrent progressive hypercalcemia) or with advanced disease. Currently
available hypocalcemic agents have little effect in decreasing the mortality
rate among patients with hypercalcemia of malignancy. Although there is some
disagreement among investigators who have evaluated survival among patients
with cancer-related hypercalcemia,[59-62] it has been observed that 50% of
patients with hypercalcemia die within 1 month and 75% within 3 months after
starting hypocalcemic treatment. In the same study, patients with
hypercalcemia who responded to specific antineoplastic treatment were found to
have a slightly greater survival advantage over nonresponders. Other
prognostic variables shown to correlate with longer survival included serum albumin concentration (direct correlation), serum calcium
concentrations after treatment (inverse correlation), and age (inverse
correlation).[5] In contrast with their modest effect on survival, marked but
differential response rates were observed after hypocalcemic treatments as a
factor of symptom type. The most substantial improvements occurred in
renal- and central nervous system–related symptoms (nausea, vomiting, and
constipation). Symptoms of anorexia, malaise, and fatigue improved, but less
completely.[5]
References
-
Warrell RP Jr: Metabolic emergencies. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers, 1997, pp 2486-93.
-
Bilezikian JP: Management of acute hypercalcemia. N Engl J Med 326 (18): 1196-203, 1992.
[PUBMED Abstract]
-
Theriault RL: Hypercalcemia of malignancy: pathophysiology and implications for treatment. Oncology (Huntingt) 7 (1): 47-50; discussion 52-5, 1993.
[PUBMED Abstract]
-
Mundy GR: Pathophysiology of cancer-associated hypercalcemia. Semin Oncol 17 (2 Suppl 5): 10-5, 1990.
[PUBMED Abstract]
-
Ralston SH, Gallacher SJ, Patel U, et al.: Cancer-associated hypercalcemia: morbidity and mortality. Clinical experience in 126 treated patients. Ann Intern Med 112 (7): 499-504, 1990.
[PUBMED Abstract]
-
Ritch PS: Treatment of cancer-related hypercalcemia. Semin Oncol 17 (2 Suppl 5): 26-33, 1990.
[PUBMED Abstract]
-
Suki WN, Yium JJ, Von Minden M, et al.: Acute treatment of hypercalcemia with furosemide. N Engl J Med 283 (16): 836-40, 1970.
[PUBMED Abstract]
-
Ignoffo RJ, Tseng A: Focus on pamidronate: a biphosphonate compound for the treatment of hypercalcemia of malignancy. Hosp Formul 26 (10): 774-86, 1991.
-
Warrell RP Jr: Etiology and current management of cancer-related hypercalcemia. Oncology (Huntingt) 6 (10): 37-43; discussion 43, 47-50, 1992.
[PUBMED Abstract]
-
Coleman RE: Bisphosphonate treatment of bone metastases and hypercalcemia of malignancy. Oncology (Huntingt) 5 (8): 55-60; discussion 60-2, 65, 1991.
[PUBMED Abstract]
-
McCloskey EV, Yates AJ, Beneton MN, et al.: Comparative effects of intravenous diphosphonates on calcium and skeletal metabolism in man. Bone 8 (Suppl 1): S35-41, 1987.
[PUBMED Abstract]
-
Mautalen C, Gonzalez D, Blumenfeld EL, et al.: Spontaneous fractures of uninvolved bones in patients with Paget's disease during unduly prolonged treatment with disodium etidronate (EHDP). Clin Orthop (207): 150-5, 1986.
[PUBMED Abstract]
-
Fleisch H: Bisphosphonates. Pharmacology and use in the treatment of tumour-induced hypercalcaemic and metastatic bone disease. Drugs 42 (6): 919-44, 1991.
[PUBMED Abstract]
-
Fenton AJ, Gutteridge DH, Kent GN, et al.: Intravenous aminobisphosphonate in Paget's disease: clinical, biochemical, histomorphometric and radiological responses. Clin Endocrinol (Oxf) 34 (3): 197-204, 1991.
[PUBMED Abstract]
-
Adamson BB, Gallacher SJ, Byars J, et al.: Mineralisation defects with pamidronate therapy for Paget's disease. Lancet 342 (8885): 1459-60, 1993.
[PUBMED Abstract]
-
Boyce BF, Adamson BB, Gallacher SJ, et al.: Mineralisation defects after pamidronate for Paget's disease. Lancet 343 (8907): 1231-2, 1994.
[PUBMED Abstract]
-
Gucalp R, Ritch P, Wiernik PH, et al.: Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia. J Clin Oncol 10 (1): 134-42, 1992.
[PUBMED Abstract]
-
Novartis Pharmaceuticals Corporation.: Aredia: package insert. May 1998.
-
Elomaa I, Blomqvist C, Porkka L, et al.: Diphosphonates for osteolytic metastases. Lancet 1 (8438): 1155-6, 1985.
[PUBMED Abstract]
-
Kerdudo C, Aerts I, Fattet S, et al.: Hypercalcemia and childhood cancer: a 7-year experience. J Pediatr Hematol Oncol 27 (1): 23-7, 2005.
[PUBMED Abstract]
-
Nussbaum SR, Younger J, Vandepol CJ, et al.: Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: comparison of 30-, 60-, and 90-mg dosages. Am J Med 95 (3): 297-304, 1993.
[PUBMED Abstract]
-
Burckhardt P, Thiébaud D, Perey L, et al.: Treatment of tumor-induced osteolysis by APD. Recent Results Cancer Res 116: 54-66, 1989.
[PUBMED Abstract]
-
Bounameaux HM, Schifferli J, Montani JP, et al.: Renal failure associated with intravenous diphosphonates. Lancet 1 (8322): 471, 1983.
[PUBMED Abstract]
-
Walker P, Watanabe S, Lawlor P, et al.: Subcutaneous clodronate. Lancet 348 (9023): 345-6, 1996.
[PUBMED Abstract]
-
Walker P, Watanabe S, Lawlor P, et al.: Subcutaneous clodronate: a study evaluating efficacy in hypercalcemia of malignancy and local toxicity. Ann Oncol 8 (9): 915-6, 1997.
[PUBMED Abstract]
-
Ostenstad B, Andersen OK: Disodium pamidronate versus mithramycin in the management of tumour-associated hypercalcemia. Acta Oncol 31 (8): 861-4, 1992.
[PUBMED Abstract]
-
Ralston SH, Gardner MD, Dryburgh FJ, et al.: Comparison of aminohydroxypropylidene diphosphonate, mithramycin, and corticosteroids/calcitonin in treatment of cancer-associated hypercalcaemia. Lancet 2 (8461): 907-10, 1985.
[PUBMED Abstract]
-
Thiébaud D, Jacquet AF, Burckhardt P: Fast and effective treatment of malignant hypercalcemia. Combination of suppositories of calcitonin and a single infusion of 3-amino 1-hydroxypropylidene-1-bisphosphonate. Arch Intern Med 150 (10): 2125-8, 1990.
[PUBMED Abstract]
-
Ralston SH, Gallacher SJ, Dryburgh FJ, et al.: Treatment of severe hypercalcaemia with mithramycin and aminohydroxypropylidene bisphosphonate. Lancet 2 (8605): 277, 1988.
[PUBMED Abstract]
-
Parsons V, Baum M, Self M: Effect of mithramycin on calcium and hydroxyproline metabolism in patients with malignant disease. Br Med J 1 (538): 474-7, 1967.
[PUBMED Abstract]
-
Kennedy BJ: Metabolic and toxic effects of mithramycin during tumor therapy. Am J Med 49 (4): 494-503, 1970.
[PUBMED Abstract]
-
Perlia CP, Gubisch NJ, Wolter J, et al.: Mithramycin treatment of hypercalcemia. Cancer 25 (2): 389-94, 1970.
[PUBMED Abstract]
-
Ashby MA, Lazarchick J: Acquired dysfibrinogenemia secondary to mithramycin toxicity. Am J Med Sci 292 (1): 53-5, 1986.
[PUBMED Abstract]
-
Benedetti RG, Heilman KJ 3rd, Gabow PA: Nephrotoxicity following single dose mithramycin therapy. Am J Nephrol 3 (5): 277-8, 1983 Sep-Oct.
[PUBMED Abstract]
-
Fillastre JP, Maitrot J, Canonne MA, et al.: Renal function and alterations in plasma electrolyte levels in normocalcaemic and hypercalaemic patients with malignant diseases, given an intravenous infusion of mithramycin. Chemotherapy 20 (5): 280-95, 1974.
[PUBMED Abstract]
-
Purpora D, Ahern MJ, Silverman N: Toxic epidermal necrolysis after mithramycin. N Engl J Med 299 (25): 1412, 1978.
[PUBMED Abstract]
-
Bashir Y, Tomson CR: Cardiac arrest associated with hypokalaemia in a patient receiving mithramycin. Postgrad Med J 64 (749): 228-9, 1988.
[PUBMED Abstract]
-
Ahr DJ, Scialla SJ, Kimbali DB Jr: Acquired platelet dysfunction following mithramycin therapy. Cancer 41 (2): 448-54, 1978.
[PUBMED Abstract]
-
Margileth DA, Smith FE, Lane M: Sudden arterial occlusion associated with mithramycin therapy. Cancer 31 (3): 708-12, 1973.
[PUBMED Abstract]
-
Warrell RP Jr, Murphy WK, Schulman P, et al.: A randomized double-blind study of gallium nitrate compared with etidronate for acute control of cancer-related hypercalcemia. J Clin Oncol 9 (8): 1467-75, 1991.
[PUBMED Abstract]
-
Warrell RP Jr, Lovett D, Dilmanian FA, et al.: Low-dose gallium nitrate for prevention of osteolysis in myeloma: results of a pilot randomized study. J Clin Oncol 11 (12): 2443-50, 1993.
[PUBMED Abstract]
-
Mundy GR, Rick ME, Turcotte R, et al.: Pathogenesis of hypercalcemia in lymphosarcoma cell leukemia. Role of an osteoclast activating factor-like substance and a mechanism of action for glucocorticoid therapy. Am J Med 65 (4): 600-6, 1978.
[PUBMED Abstract]
-
Ralston SH, Fogelman I, Gardiner MD, et al.: Relative contribution of humoral and metastatic factors to the pathogenesis of hypercalcaemia in malignancy. Br Med J (Clin Res Ed) 288 (6428): 1405-8, 1984.
[PUBMED Abstract]
-
Potts JT: Diseases of the parathyroid gland and other hyper- and hypocalcemic disorders. In: Isselbacher KJ, Braunwald E, Wilson JD, et al., eds.: Principles of Internal Medicine. New York: McGraw-Hill, 1994, pp. 2151-71.
-
Massry SG, Mueller E, Silverman AG, et al.: Inorganic phosphate treatment of hypercalcemia. Arch Intern Med 121 (4): 307-12, 1968.
[PUBMED Abstract]
-
Hebert LA, Lemann J Jr, Petersen JR, et al.: Studies of the mechanism by which phosphate infusion lowers serum calcium concentration. J Clin Invest 45 (12): 1886-94, 1966.
[PUBMED Abstract]
-
Shackney S, Hasson J: Precipitous fall in serum calcium, hypotension, and acute renal failure after intravenous phosphate therapy for hypercalcemia. Report of two cases. Ann Intern Med 66 (5): 906-16, 1967.
[PUBMED Abstract]
-
Goldsmith RS, Ingbar SH: Inorganic phosphate treatment of hypercalcemia of diverse etiologies. N Engl J Med 274 (1): 1-7, 1966.
[PUBMED Abstract]
-
Nolph KD, Stoltz M, Maher JF: Calcium free peritoneal dialysis. Treatment of vitamin D intoxication. Arch Intern Med 128 (5): 809-14, 1971.
[PUBMED Abstract]
-
Cardella CJ, Birkin BL, Rapoport A: Role of dialysis in the treatment of severe hypercalcemia: report of two cases successfully treated with hemodialysis and review of the literature. Clin Nephrol 12 (6): 285-90, 1979.
[PUBMED Abstract]
-
Schreiner GE, Teehan BP: Dialysis of poisons and drugs - annual review. Trans Am Soc Artif Intern Organs 18 (0): 563-99, 1972.
[PUBMED Abstract]
-
Stoltz ML, Nolph KD, Maher JF: Factors affecting calcium removal with calcium-free peritoneal dialysis. J Lab Clin Med 78 (3): 389-98, 1971.
[PUBMED Abstract]
-
Seyberth HW, Segre GV, Morgan JL, et al.: Prostaglandins as mediators of hypercalcemia associated with certain types of cancer. N Engl J Med 293 (25): 1278-83, 1975.
[PUBMED Abstract]
-
Seyberth HW, Segre GV, Hamet P, et al.: Characterization of the group of patients with the hypercalcemia of cancer who respond to treatment with prostaglandin synthesis inhibitors. Trans Assoc Am Physicians 89: 92-104, 1976.
[PUBMED Abstract]
-
Coombes RC, Neville AM, Bondy PK, et al.: Failure of indomethacin to reduce hypercalcemia in patients with breast cancer. Prostaglandins 12 (6): 1027-35, 1976.
[PUBMED Abstract]
-
Brenner DE, Harvey HA, Lipton A, et al.: A study of prostaglandin E2, parathormone, and response to indomethacin in patients with hypercalcemia of malignancy. Cancer 49 (3): 556-61, 1982.
[PUBMED Abstract]
-
Lad TE, Mishoulam HM, Shevrin DH, et al.: Treatment of cancer-associated hypercalcemia with cisplatin. Arch Intern Med 147 (2): 329-32, 1987.
[PUBMED Abstract]
-
List A: Malignant hypercalcemia. The choice of therapy. Arch Intern Med 151 (3): 437-8, 1991.
[PUBMED Abstract]
-
Warrell RP Jr, Israel R, Frisone M, et al.: Gallium nitrate for acute treatment of cancer-related hypercalcemia. A randomized, double-blind comparison to calcitonin. Ann Intern Med 108 (5): 669-74, 1988.
[PUBMED Abstract]
-
Blomqvist CP: Malignant hypercalcemia--a hospital survey. Acta Med Scand 220 (5): 455-63, 1986.
[PUBMED Abstract]
-
Mundy GR, Martin TJ: The hypercalcemia of malignancy: pathogenesis and management. Metabolism 31 (12): 1247-77, 1982.
[PUBMED Abstract]
-
Fisken RA, Heath DA, Bold AM: Hypercalcaemia--a hospital survey. Q J Med 49 (196): 405-18, 1980 Autumn.
[PUBMED Abstract]
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