Hypercalcemia, Emergency Medicine

Basics

Description

Severity depends on serum calcium level and rate of increase
0.1 " 1% of patients on routine screening
Most cases mild (<12 mg/dL) and asymptomatic
Hypercalcemic crisis, usually >14 mg/dL, causes serious signs and symptoms
Calcium in bloodstream in 3 forms:
- Ionized: 45%
- Bound to protein (primarily albumin): 40%
- Bound to other anions: 15%
Ionized calcium " only physiologically active form

Etiology

Primary hyperparathyroidism
Malignancy
Miscellaneous

Diagnosis

Signs and Symptoms

History

Neurologic:
- Headache
- Fatigue, lethargy
- Weakness
- Difficulty concentrating
- Confusion
- Depression, paranoia
Renal:
- Polyuria, polydipsia
- Complaints related to oliguric renal failure
- Chronic, complaints related to:
  - Renal calculi
  - Nephrocalcinosis
  - Interstitial nephritis
GI:
- Anorexia
- Nausea, vomiting
- Abdominal pain
- Constipation
- Chronic, complaints related to:
  - Peptic ulcer disease
  - Pancreatitis
Dermatologic:
- Pruritus
- Mnemonic: "Stones, Bones, Groans, Thrones and Psychiatric Overtones, " "bones " refers to bone pain and "thrones " refers to polyuria.

Failure to thrive
Slow development
Mental retardation may ensue

Physical Exam

Neurologic:
- Irritability
- Lethargy
- Stupor
- Coma
- Hyporeflexia
Cardiovascular:
- Hypotension, if severely volume depleted, or HTN
- Sinus bradycardia
- Cardiac arrest with severe hypercalcemia (rare)
Renal:
- Signs of dehydration
Dermatologic:
- Band keratopathy
- Ectopic calcification

Characteristic facies: Pug nose, fat nasal bridge, "cupids bow " upper lip
Hypotonia

Essential Workup

Ionized and total serum calcium levels, albumin levels:
- Normal total calcium level is <10.5 mg/dL
- Must correct for calcium that is protein bound, primarily to albumin
- Corrected total calcium (mg/dL) = measured total calcium (mg/dL) + 0.8 [4.0 " albumin concentration (g/dL)]
Electrolytes, BUN/creatinine, glucose
- Possible oliguric renal failure
ECG:
- Shortening of QT interval
- Prolongation of PR interval
- QRS widening
- Accentuated side effects of digoxin
- Sinus bradycardia, bundle branch block, AV block, cardiac arrest with severe hypercalcemia (rare)
- Can cause Osborn J-wave at the end of QRS complex that is usually associated with hypothermia

Diagnosis Tests & Interpretation

Lab

Phosphate
Protein
Urinalysis
Parathyroid hormone (PTH) level:
- If elevated or high normal, likely primary hyperparathyroidism.
- If <20 pg/mL, consider testing PTH-related peptide and vitamin D metabolites.
Vitamin D metabolites, if suspected
- 25-hydroxy vitamin D (calcidiol):
  - If elevated, consider exogenous source (i.e., meds, vitamins, supplements).
- 1,25-dihydroxy vitamin D (calcitriol):
  - If elevated, consider lymphoma or sarcoid
Digoxin level, if taking
Thyroid function tests

Imaging

CT head for altered mental status
Chest x-ray and workup for occult malignancy, if no other cause for hypercalcemia

Diagnostic Procedures/Surgery
Parathyroidectomy:

For primary hyperparathyroidism resulting in symptomatic or severe hypercalcemia
Some patients require urgent parathyroidectomy.

Differential Diagnosis

Primary hyperparathyroidism:
- Most common cause among outpatients
- Parathyroid adenoma 80%; hyperplasia 15%; carcinoma 5%
- Usually mild, <11.2 mg/dL
- Patients can be asymptomatic or have chronically elevated calcium
- Increased bone resorption, relative decrease in calcium excretion, increased intestinal calcium absorption
Malignancy:
- Most common cause in hospitalized patients
- Usually a rapid rise in serum calcium
- Patients are more often symptomatic
- Higher serum calcium concentrations
- Most common paraneoplastic complication of cancer
- Common tumors causing hypercalcemia: Breast, lung, colon, stomach, cervix, uterus, ovary, kidney, bladder, head and neck, multiple myeloma, and lymphoma
- Most commonly from production of PTH-related protein with similar actions
- May result from production of other bone-resorbing substances by tumor
- May result from local effects of osteolytic skeletal metastasis
Miscellaneous:
- Hypercalcemia associated with granulomatous diseases
- Excessive calcium supplements
- Thiazide diuretics causing increased renal reabsorption
- Familial hypocalciuric hypercalcemia
- Acute vitamin A intoxication
- Exogenous vitamin D intake
- Milk-alkali syndrome from excessive ingestion of calcium and nonabsorbable antacids, such as milk or calcium carbonate
- Long-term lithium therapy
- Renal transplantation
- Hyperthyroidism
- Acute tubular necrosis

Differential diagnosis: Differences from adults:

Primary hyperparathyroidism:
- Less common than in adults
Infantile hypercalcemia:
- Uncertain cause
- Possibly hypersensitivity and in utero excessive exposure to vitamin D
Immobilization hypercalcemia:
- Typically adolescent who is growing rapidly
- Prolonged immobilization, especially in traction, leads to hypercalciuria and then hypercalcemia
- Presumably from increased bone resorption with decreased or arrested bone mineralization

Treatment

Pre-Hospital

Routine stabilization techniques

Initial Stabilization/Therapy

ABCs, IV access, oxygen, cardiac monitor
0.9% NS 1 L bolus (20 mL/kg) for hypotension or severe dehydration
Naloxone, thiamine, D50W (or stat serum glucose measurement) for altered mental status

Ed Treatment/Procedures

General:
- Immediate therapy for severe hypercalcemia (corrected total >14 mg/dL) regardless of symptoms, or for symptomatic hypercalcemia
- Asymptomatic, mild hypercalcemia does not require emergency treatment
Restoration of IV volume:
- Isotonic saline:
  - 200 " 300 mL/hr adjusted to maintain urine output 100 " 150 mL/hr
- Often need 2 " 5 L/day
- Bedside vigilance necessary to prevent fluid overload
- Correct other electrolyte abnormalities
- Cardiovascular status of patient may necessitate central venous pressure monitoring to adjust fluid administration rates
Renal elimination:
- After volume expansion and if needed to avoid overload, administer loop diuretics (furosemide)
- Avoid thiazide diuretics
- May need peritoneal or hemodialysis against a low calcium dialysate in renal failure
Inhibition of osteoclastic activity:
- Reduce mobilization of calcium from bone
- Administer drug therapy when corrected calcium level >14 mg/dL or signs or symptoms
- First-line drug therapy:
  - Bisphosphonates: Pamidronate (more potent and possibly less toxic), etidronate
  - Calcitonin: Rapid onset but modest decrease in levels
- Other potential drug therapy:
  - Plicamycin: Efficacious but numerous side effects
  - Hydrocortisone: Especially useful with malignancies, granulomatous disorders, or vitamin D intoxication
- Encourage ambulation in appropriate patients
Treat underlying disorder:
- Parathyroidectomy for primary hyperparathyroidism resulting in symptomatic or severe hypercalcemia
- Discontinue medication if cause of hypercalcemia

Medication

First Line

Calcitonin: 4 IU/kg IM/SC q12h
Etidronate: 7.5 mg/kg over 4 hr daily for 3 " 7 days IV
Furosemide: 10 " 40 mg q6 " 8h (peds: 1 " 2 mg/kg) IV
Pamidronate: Single 2 " 24 hr infusion of 60 " 90 mg IV (peds: Consult pediatrician)

Second Line

Gallium nitrate: Continuous infusion of 200 mg/m2/d for 5 days IV
Hydrocortisone: 200 " 400 mg/d IV for 3 " 5 days (peds: Consult pediatrician)
Plicamycin: 25 Όg/kg/d over 4 " 6 hr IV for 3 " 8 doses

In infants, loop diuretics are rarely necessary and possibly harmful as they may decrease glomerular filtration rate and worsen hypercalcemia
Bisphosphonates have not been extensively studied in pediatrics but do appear to be safe

Follow-Up

Disposition

Admission Criteria

Corrected total calcium level >13 mg/dL
Signs or symptoms attributed to hypercalcemia, especially EKG changes
Monitored bed or ICU for corrected level >14 or serious signs and symptoms

Discharge Criteria
Corrected calcium level <13 mg/dL and no signs or symptoms of hypercalcemia
Issues for Referral

Rapid follow-up arranged to determine cause and long-term therapy
Consultation with endocrinologist should be considered

Follow-Up Recommendations

Fluid hydration
Watch for mental status changes

Pearls and Pitfalls

Make decisions based on symptoms or corrected Ca levels
All patients with serum Ca >14 mg/dL require treatment regardless of symptoms
Pay careful attention to EKG changes
Careful monitoring is required for patients receiving IV volume repletion:
- They often require a large volume of fluid but care must be taken to avoid volume overload

Additional Reading

Ariyan CE, Sosa JA. Assessment and management of patients with abnormal calcium. Crit Care Med. 2004;32(suppl 4):S146 " S154.
Inzucchi SE. Management of hypercalcemia. Diagnostic workup, therapeutic options for hyperparathyroidism and other common causes. Postgrad Med. 2004;115:27 " 36.
Lietman SA, Germain-Lee EL, Levine MA. Hypercalcemia in children and adolescents. Curr Opin Pediatr. 2010;22(4):508 " 515.
Marx JA, Hockberger RS, Walls RM, eds. Rosens Emergency Medicine. Philadelphia, PA: Elsevier; 2009.

Codes

ICD9

275.42 Hypercalcemia
275.49 Other disorders of calcium metabolism
588.89 Other specified disorders resulting from impaired renal function
592.0 Calculus of kidney

ICD10

E83.52 Hypercalcemia
E83.59 Other disorders of calcium metabolism
N25.89 Oth disorders resulting from impaired renal tubular function
N20.0 Calculus of kidney

SNOMED

66931009 Hypercalcemia (disorder)
33763006 Hypercalcemic nephropathy (disorder)
48638002 nephrocalcinosis (disorder)
95570007 Kidney stone (disorder)

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