General Approach to Treatment

Therapeutic options for the treatment of hypercalcemia should be directed toward the level of corrected serum calcium and the presence of symptoms (Fig. 99-5). Hypercalcemia may be classified as mild (corrected calcium equal to 10.5-11.9 g/dL [2.6-3 mmol/L]), moderate (12-13.9 g/dL [3-3.5 mmol/L]), and severe (greater than 14 g/dL

[3.5 mmol/L]). Adequate treatment of mild or asymptomatic hypercalcemia may be achieved on an outpatient basis with nonpharmacologic measures. Moderate to severe or symptomatic hypercalcemia almost always requires pharmacologic intervention.

Nonpharmacologic Therapy

Calciuric therapy in the form of hydration is a key component to the treatment of hypercalcemia, regardless of severity or presence of symptoms.49 Mild or asymptomatic patients may be encouraged to increase oral fluid intake (3-4 L/day). Patients with moderate to severe or symptomatic hypercalcemia should receive normal saline at 200 to 500 mL/hour according to dehydration and cardiovascular status. Patients should be encouraged to ambulate as much as possible since immobility enhances bone resorption. Although calcium should be discontinued from parenteral feeding solutions, oral calcium supplementation minimally contributes to hypercalcemia, unless it is mediated by vitamin D. In these cases, oral calcium should be discontinued. Finally, agents that may contribute to hypercalcemia (thiazide diuretics, vitamin D, lithium) or decrease renal function (NSAIDs) should be discontinued. Dialysis may be used in refractory cases or patients who cannot tolerate aggressive saline hydration.

Hypercalcemia Related Malignancy

FIGURE 99-4. Pathophysiology of the hypercalcemia of malignancy. (Ca , calcium; IL-1, inter-leukin 1; IL-2, interleukin 2; TGF-3, transforming growth factor ¡; TNF-a, tumor necrosis factor a; PTHrP, parathyroid hormone-related protein.)

Clinical Presentation and Diagnosis of Hypercalcemia General

• Presence of symptoms depends not only on the calcium level but the rapidity of onset

• Normal calcium level is 8.5 to 10.5 g/dL (2.1 to 2.6 mmol/L) (varies by lab)

• Serum calcium level must be corrected for albumin level using the following formula:

• Corrected calcium = (Measured calcium-Measured albumin) + 4 Signs and Symptoms

• Five primary organ systems may be affected: GI: Anorexia; nausea; vomiting; constipation Musculoskeletal: weakness; bone pain; fatigue; ataxia CNS: Confusion; headache; lethargy; seizures; coma Genitourinary: Polydipsia; polyuria; renal failure Cardiac: Bradycardia; ECG abnormalities; arrhythmias Laboratory Tests

• Elevated corrected serum calcium level (greater than or equal to 10.5 g/dL (2.6 mmol/L), serum albumin, low to normal serum phosphate

• Patient may have elevated BUN and serum creatinine

• Elevated alkaline phosphatase may indicate bone destruction

• ECG may indicate prolonged PR interval, shortened QT interval, widened T wave Other Diagnostic Tests

• Rule out other causes of hypercalcemia including primary hyperparathyroidism, hy-perthyroidism, vitamin D intoxication, chronic renal failure

Pharmacologic Therapy

Multiple pharmacologic interventions are available for the treatment of hypercalcemia (Table 99-13). Furosemide 20 to 40 mg/day may be added to hydration once rehydration has been achieved to avoid fluid overload and enhance renal excretion of calcium. Although effective in relieving symptoms, hydration and diuretics are temporary measures that are useful until the onset of antiresorptive therapy, thus hydration and antiresorptive therapy should be initiated simultaneously.

Hypercalcemia Treatment
FIGURE 99-5. Treatment algorithm for the hypercalcemia of malignancy.

Table 99-13 Treatment Options for Hypercalcemia of Malignancy

Reduction In

i«fu m ÎikNum






(jlcHirtc ihrfapy

IV normal yilifM>

300-500 tnut

2A-A H


ftS-2 mgftlt.

Avoid Hind r™urkvv1, monitor


eiec tnolylei



■f hous


Monitor fix hypokalemia'.




ùO-tÛ mq IVqvÇï



iieatfn than

Nadir mm leen until aflet 1 -)


2-24 horns'


1 nig/dL

days; may cauw fever, rwial

/uktlionir .Kid

J rrvj IV owe li

>1 -IS

lit nwlj

tüe-irei than

dysf uiKifciif pamidronjie kss



1 mg/dL



htdrif»« équivalent] 50-IÛD mg dally




Monitof tor hypotglKcmk ¡momma, ¡rrmiii™ijppiwwMi

¿at n«iin

i-MWrktjSÖralM every 6-12 hourt

1-A Ituuri


i-3 mqAil

Salmon (iMiwd foimulanhn pn-tnicd; l unit lcit-tftnc iccom men fled; iin he given In ipfud failure; may rauie flmhir kj. IUIHB

Gallium nitrate

Iffi-JMmg/m'CIV daily ta Sdjyi.


[Jo nol ¿dmlnlilei II creatinine grLMK-T thjn i.5 mtfftJL; ma/ curse wai failure

CIV. itnnifmöui tv infusion; IM. imiaiftuK Järly; 5C. iUbCuljncomly.

t# mg üf Pamidronate may be used in imalier tali«« o* in ttxwe rMiierits with tnikl hypertJtjWii.> of it^ai tftiiunttion, May use longer infmion time In parleni% wnH renal dyilgnakjn.

CIV. itnnifmöui tv infusion; IM. imiaiftuK Järly; 5C. iUbCuljncomly.

t# mg üf Pamidronate may be used in imalier tali«« o* in ttxwe rMiierits with tnikl hypertJtjWii.> of it^ai tftiiunttion, May use longer infmion time In parleni% wnH renal dyilgnakjn.

The antiresorptive therapy of choice for hypercalcemia of malignancy is a bi-sphosphonate. Because of poor oral bio-availability, only IV agents should be used. Pamidronate and zoledronic acid are most commonly utilized and are potent inhibitors of osteoclast activity.50 The choice of bisphosphonate is a difficult one; zoledronic acid is more efficacious in terms of response rate and longer duration of normocal-cemia, but is approximately four times more expensive.51 Regardless of selection, the bisphosphonates should be administered at diagnosis due to their delayed onset of action.

Calcitonin is the drug of choice in cases of emergent hypercalcemia (patients with life-threatening ECG changes, arrhythmias, or CNS effects) due to its rapid onset of action. Calcitonin inhibits osteoclast activity and decreases renal tubular calcium resorption. Corticosteroids are useful in patients with steroid-responsive malignancies, such as lymphomas or multiple myeloma, and may delay tachyphylaxis to calcitonin. Gallium nitrate was also recently reapproved for treatment, although the 5-day administration regimen and risk of nephrotoxicity limit its use.

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