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 for
most 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 cause
C 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 (<100 mEq/L)
suggests hypercalcemia of
malignancy.
C C C C
13 mg/dL
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 hours
C 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 (1
st
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 advanced
malignancies
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
16
th
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