Malignant Hypercalcemia

JV Divatia

Professor and Head

Department of Anaesthesia, Critical Care and Pain

Tata Memorial Hospital

Mumbai, India

Physiologic Role of Ca

Contraction of skeletal, cardiac, and smooth muscles

Blood clotting;

Transmission of nerve impulses

Excitable cells, such as neurons, are very sensitive to changes in calcium ion concentrations

Hypercalcemia : progressive depression of the nervous system

Hypocalcemia : CNS excitation

Distribution of Ca

0.1 per cent of the total body Ca is in

the ECF

1 per cent is in the cells

Rest is stored in bones

bones can serve as large reservoirs

Ionic Ca is the form that is important formost functions of calcium in the body

Case

62 y/o male with h/o squamous cell carcinoma of tonsillar pillar

treated 18 months prior with combined chemo/XRT

presents with 2 weeks of worsening fatigue, anorexia, polyuria with occasional

incontinence, constipation, and muscle

weakness

Examination Fluctuating level of consciousness

Vitals normal, no fever

Dehydrated

Coarse upper airway sounds

No other pertinent findings

Investigations

CBC normal

Mildly elevated BUN and Cr

Normal LFTs

Standard electrolytes normal

Concern of pneumonia

Chest x-ray ordered

Multiple pulmonary metastases

Calcium checked

4.5 mmol / L

Hypercalcemia

Epidemiology

Occurs in about 10 to 20% of patients with cancer

Both solid tumors and leukemias

Most common

Breast

Lung

Multiple myeloma

Pathogenesis

Three mechanisms

Osteolytic metastases with local cytokine release

Tumor secretion of parathyroid hormone-related protein (PTHrP)

Tumor production of calcitriol

Osteolytic Metastases

Osteolytic Metastases

Breast cancer

Non-small cell lung cancer

Cytokines released

Tumor necrosis factor

Interleukin-1

Stimulate osteoclast precursor differentiation into mature osteoclasts

Leading to more bone breakdown and release of calcium

Parathyroid HormoneRelated Protein

Responsible for most instances of hypercalcemia of malignancy

Little influence on calcium homeostasis

except in disease states, when large tumors, especially of the squamous cell type, lead to massive

overproduction of the hormone

Developmental influences on fetal bone development and in adult physiology

PTH-Related Protein Most common in patients with non-

metastatic tumors

Called humoral hypercalcemia of malignancy

Secretion of PTH itself is a rare event

PTHrP binds to same receptor as PTH and stimulates adeynylate cyclase activity

Increased bone resorption

Increases kidney calcium reabsorption and phosphate excretion

Calcitriol

Hodgkins disease (mechanism in majority)

Non-Hodgkins (mechanism in 1/3)

Usually responds to glucocorticoid therapy

Diagnosis

Hypercalcemia : Manifestations

Gastrointestinal

Constipation is most common

Anorexia, Vague abdominal pain

Rarely can lead to pancreatitis

Renal

Nephrolithiasis

More common in hyperparathyroidism

Nephrogenic diabetes insipidus

Polyuria, polydipsia

Chronic renal failure

Longstanding high Ca

Usually nonspecific

Hypercalcemia : Manifestations

Cardiovascular

Short QT interval

Supraventricular arrhythmias

Ventricular arrhythmias

Neuropsychiatric

Anxiety

Depression

Cognitive dysfunction

Delirium

Psychosis

Hallucinations

Somnolence

Coma

ECG changes in Hypercalcemia

C C C C

Suspect Hypercalcemia.

In any cancer patient presenting with acute pancreatitis, unexplained

somnolence or polyuria

Due to underlying malignancy in any patient presenting with acute pancreatitis,

unexplained somnolence or polyuria

Malignancy must be ruled out in patients that present with a very high calcium and

no other obvious causeC C C C

Investigations

Total Ca 10.8 mg/dL

Albumin = 1.2g/dL

Na 138 mmol/L

Cl 90 mmol/L

K 5.6 mmol/L

Corrected Ca ?

Ionized Ca

Total Ca

Calculate Corrected Ca

Total Ca + [0.8(4.0 albumin)].

Serum creatinine, electrolytes, & alkaline phosphatase.

A low serum Cl (

Treatment

Aims

Lower serum calcium concentration

Treat complications if present

Treat underlying disease

Hydration is of utmost importance in these patients, and intravenous saline should be given

rapidly once hypercalcemia is confirmed.

Hypercalcemia causes hypovolemia and hypovolemia aggravates hypercalcemia

C C C C

Hydration!

Volume

Large volume of normal Saline administration

Expands intravascular volume

Increases calcium excretion

Inhibition of proximal tubule and loop reabosrption

Reduces passive reabsorption of calicum

Follow fluid status b/c of danger of fluid overload

Fluid therapy

Give 1 L NS over first hour, then at lower rate till

hypovolemia is corrected

Establish urine output

Exercise caution: Close CVS monitoring

Renal impairment

Cardiovascular dysfunction

C C C C

Start diuretics

Only after VOLUME REPLETION

hypovolemia causes renal hypoperfusion

hampering calcium excretion.

Consider loop diuretics

Very useful if hypervolemia exists

C C C C

Start specific therapy

Bisphosphonates

Pamidronate: 6090 mg IV 24 hours OR

Zoledronic acid: 4 mg IV over 15 minutes

Calcitonin

Useful as rapid onset

48 IU/Kg SC or IV every 12 hours

Glucocorticoids (especially in lymphoma)

Prednisolone: 60 mg/day PO or

Hydrocortisone: 100 mg IV every 6 hoursC C C C

Calcitonin

Salmon calcitonin

Increases renal excretion of calcium

Decreases bone reabsorption by interfering with osteoclast maturation

Weak agent

Works the fastest

Bisphosphonates Adsorb to the surface of bone

hyroxyapatite

Interfere with osteoclast activity

Cytotoxic to osteoclasts

Inhibit calcium release from bone

Three commonly used

Pamidronate

Zoledronic acid

Etidronate (1st generation, weaker)

Bisphosphonates More potent than calcitonin

Maxium effect occurs in 2 to 4 days

Trend to use of IV zoledronic acid in the acute situation

Both are can be renal toxic

More potent than pamidronate

Administered over a shorter period of time (15 minutes vs. 2 hours)

Side effect

Osteonecrosis of the jaw

Recent case reports of jaw bone necrosis in patients on pamidronate

EDUCATION needed

Gallium Nitrate

Effective

More potential for nephrotoxicity

Rarely used

Dialysis Last resort

Dialysis fluid with little or no calcium is effective

Useful when patients cant tolerate large volume resuscitation

If calcium needs to be correct emergently

Management

Decrease dietary intake of calcium

Treat the Cause

Chemotherapy or Radiation if feasible

Evaluate prognosis

Hypercalcemia occurs in many advancedmalignancies

C C C C

C C C C

High index of suspicion

Measure serum calcium

Mild hypercalcemia

11 to 12 mg/dL

Asymptomatic

Hydration with saline

Eliminate dietary sources

of calcium & thiazide

diuretics

Moderate hypercalcemia

12 to 18 mg/dL

Symptomatic

Hydration

Loop diuretics

Bisphosphonate

Eliminate dietary calcium

thiazide diuretics

Severe hypercalcemia

> 18 mg/dL

Hydration

Loop diuretics

Calcitonin

Bisphosphonates

Steriods

Hemodialysis

Eliminate dietary Calcium

thiazide diuretics

Measure serum calcium and other

electrolytes particularly serum K

at least BD till Ca decreasing

Treatment of Hypercalcemia

16th APACCM

February 14-18, Jaipur, India

Physical Findings

Usually not specific

Dehydration secondary to diuresis caused by the hypercalcemia

Corneal deposition of calcium

band keratopathy on slit lamp exam

Diagnosis

Malignancy must be ruled out in patients that present with a very high calcium and

no other obvious cause