EMERGENCY TREATMENT OF
SEVERE HYPERCALCEMIA
Binu Abi, PharmD
UW Medicine
PGY1 Pharmacy Resident
January 29th, 2015
Case
• LC
• 65 y/o M Wt 65 kg
• CC
• Presented to ED with complaints of dizziness, auditory/visual
hallucinations, abdominal pain, polyuria in setting of starting
duloxetine 10 days ago.
• PMH
• Alcohol abuse, depression, pancytopenia
• Home Medications
• Duloxetine
• Allergies
• Sulfa
Case
• Head CT – Normal
• Vitals: normal
• Labs
Calcium
• Essential for many important functions
• Structure
• Cell signaling
• Regulation of protein function
Intensive Care Med. 2013; 00(0):1-18.
Calcium
• 99% of total body calcium found in bone
• 0.9% intracellular
• 0.1% extracellular
• Normal total calcium: 8.5 – 10.5 mg/dL
• 50% bound to plasma protein (albumin)
• Ionized or free calcium – physiologically active form regulated by
homeostasis
• Corrected calcium = (4- serum albumin) x 0.8 + serum calcium
• Normal ionized calcium: 4.4 – 5.4 mg/dL
Best Pract Res Clin Endocrinol Metab. 2003; 17(4):623-51
Calcium Homeostasis
• Calcium homeostasis is
regulated by
• Parathyroid hormone (PTH)
• Vitamin D (Calcitriol)
• Calcitonin
Calcium Homeostasis – PTH
• Secreted from parathyroid gland in response
to drop in serum calcium
• Increases serum calcium
• Bone
•  resorption of calcium and phosphorus
• Kidney
•  tubular reabsorption of calcium and
phosphorus
•  vitamin D activity
• GI tract
•  intestinal absorption of calcium and
phosphorus (indirectly)
Best Pract Res Clin Endocrinol Metab. 2003; 17(4):623-51
Calcium Regulation – Vitamin D
• 25 (OH) vitamin D – Calcidiol
• Storage form
• Liver
• 1,25 (OH) vitamin D – Calcitriol
• Active form
• Activated by PTH and
hypophosphatemia through 1-alpha
hydroxylase in the kidney
• Small intestine-  absorption of calcium
and phosphorous
• Bone-  osteoclast activity
• Kidney-  calcium and phosphate
reabsorption
Best Pract Res Clin Endocrinol Metab. 2003; 17(4):623-51
Calcium Regulation – Calcitonin
• Hormone produced by thyroid gland
• Secreted when ionized calcium concentrations are high
• Reduces serum calcium
• Bone
•  osteoclastic resorption of calcium
• Kidney
•  tubular reabsorption of calcium and phosphorus
• GI tract
•  intestinal absorption of calcium and phosphorus
(indirectly)
Best Pract Res Clin Endocrinol Metab. 2003; 17(4):623-51
Hypercalcemia
• Elevated total serum concentration of calcium in blood
• Mild
• <12 mg/dL
• Moderate
• 12-14 mg/dL
• Severe
• >14 mg/dL
• Hypercalcemia crisis
• Acute elevation of total serum calcium > 15 mg/dL, acute renal
insufficiency, obtundation
Best Pract Res Clin Endocrinol Metab. 2003; 17(4):623-51
Clinical Presentation
• Varies depending on severity and rapidity of onset
• Mild to moderate- often asymptomatic
Manifestations of Hypercalcemia
Neuromuscular
Somnolence, confusion, depression, psychosis,
coma, muscle weakness
GI
Constipation, anorexia, nausea, abdominal pain,
peptic ulcer disease, pancreatitis
Renal
Decreased ability to concentrate urine, polyuria,
polydipsia, nephrolithiasis, nephrocalcinosis, renal
failure
CV
Hypertension, short QT, arrhythmias, digitalis
sensitivity
Skeletal
Osteoporosis, fracture, bone pain
Intensive Care Med. 2013; 00(0):1-18.
Causes of Hypercalcemia
• Parathyroid dependent
• Primary hyperparathyroidism
• Familial hypocalciuric
hypercalcemia
• Parathyroid independent
• Malignancy
• Medications
• Paget’s disease
• Endocrinopathies
• Granulomatous disease
• Hyperthyroidism
• Pathophysiology
•  bone resorption
•  GI absorption
•  tubular
reabsorption/ renal
excretion
Intensive Care Med. 2013; 00(0):1-18.
Primary Hyperparathyroidism
• Most common underlying etiology
• Excessive secretion of PTH despite normal levels of
calcium
• 80% due to benign parathyroid adenomas
• CKD  secondary hyperparathyroidism
• Usually presents as mild to moderate hypercalcemia
Intensive Care Med. 2013; 00(0):1-18.
Hypercalcemia of Malignancy
• 20-40% of cancer patients experience hypercalcemia
during course of disease
• Tumors secrete PTH-related protein (PTHrP)  increased
bone resorption and renal tubular reabsorption
• Most common in lung and breast carcinomas
• 40% with multiple myeloma develop hypercalcemia
• Usually presents as severe hypercalcemia
Intensive Care Med. 2013; 00(0):1-18.
Causes of Hypercalcemia – Medications
Medication
Mechanism
Thiazides
Increased renal tubular
reabsorption
Lithium
Increased GI absorption
increase bone resorption
Increased renal tubular
reabsorption
Vitamin D
Increased GI absorption
Vitamin A
Increase bone resorption
Calcium
Increased GI absorption
Milk-alkali syndrome
Aluminum/magnesium Antacids
Theophylline
Tamoxifen
Ganciclovir
Estrogen
Pharmacotherapy: A Pathophysiologic Approach, 9e
Complications of Hypercalcemia
• Progression to hypercalcemia crisis
• Renal failure
• Coma
• Life-threatening arrhythmias
• Metastatic calcification
• Osteoporosis
Pharmacotherapy: A Pathophysiologic Approach, 9e
Treatment of Severe Hypercalcemia
• Intravenous Fluids
• Diuretics
• Calcitonin
• Bisphosphonates
• Others
• Glucocorticoids
• Cinacalcet
• Denosumab
• Hydroxychloroquine
• Ketoconazole
• Gallium nitrate
Treatment – Intravenous fluids
• MOA: expands intravascular space and increases renal
excretion
• Initial repletion reverses serum calcium 1-2 mg/dL
• 3-6 L of NS during initial 24 hour period
• Caution in CHF
Best Pract Res Clin Endocrinol Metab. 2003; 17(4):623-51
Treatment – Diuretics
• Loop diuretics to promote calciuresis
• Reduces calcium reabsorption in the loop of Henle
• Furosemide 20-40 mg IV q2h after correction of dehydration
• Effect on calcium levels:  2-6 mg/dL after 24 h
• Limited evidence for use of diuretics for increased
calciuresis
• Excessive diuresis  volume depletion, hypokalemia, and
worsening hypercalcemia
• Limit use to reversal of overly aggressive fluid replacement
• Avoid thiazides! (enhances calcium resorption)
Best Pract Res Clin Endocrinol Metab. 2003; 17(4):623-51
Treatment – Calcitonin
Calcitonin
MOA
Similar to human calcitonin; antagonizes the effects of
parathyroid hormone. Inhibits osteoclastic bone
resorption; promotes the renal excretion of calcium by
decreasing tubular reabsorption
Dose
4-8 IU/kg SC/IM q6-12 h
Effect on Calcium Level  1-2 mg/dL
Pharmacokinetics
Onset: 2 h
Duration: 6-8 h
Metabolism: kidneys, blood, tissue
Bioavailability: 71% SC, 66% IM
Half-life: ~1 h
Time to peak: ~30 min
Adverse Effects
Nausea, vomiting, flushing, injection site reactions
Precaution
Effective only up to 48 h – tachyphylaxis due to
downregulation of receptors
Miacalcin injection [prescribing information]. Novartis 2014.
Treatment – Bisphosphonates
• MOA: adsorb to the surface of bone and inhibit calcium
release by interfering with osteoclast-mediated bone
resorption
• Zoledronic acid (Reclast, Zometa) – FDA approved for hypercalcemia
•
•
•
•
•
of malignancy (Zometa)
Pamidronate (Aredia) – FDA approved for hypercalcemia of
malignancy
Etidronate (Didronel)
Alendronate (Fosamax)
Risedronate (Actonel)
Ibandronate (Boniva)
Intensive Care Med. 2013; 00(0):1-18.
Treatment – Bisphosphonates
Zoledronic Acid
Pamidronate
Dose
3-4 mg IV over 15-30 min x 1
60-90 mg IV over 2-24 h x 1
Dose for renal
impairment
Mild/moderate: no adjustment
needed
Severe: evaluate risk vs benefit,
infuse longer
Evaluate risk vs benefit,
decrease dose and infuse over
4-6 h
Effect on Calcium Level
More potent than calcitonin, normocalcemia over 2-7 days
PK
Onset: 48 hours
Duration: median 33 d
Metabolism: not metabolized
Half-life: 146 h
Adverse Effects
Flu-like symptoms (fever, arthralgia, myalgia, fatigue, bone pain), ocular
inflammation (uveitis), hypocalcemia, hypophosphatemia, impaired renal
function, nephrotic syndrome, osteonecrosis of the jaw
Precaution
Pregnancy
Comments
Bisphosphonates more efficacious than placebo (Saunders, 2004)
Zoledronic acid superior to pamidronate (Major, 2001)
Onset: 24-48 h
Duration: 2-4 weeks
Metabolism: not metabolized
Half-life: 21-35 h
Time to peak: ~30 min
Pregnancy
Treatment – Other
• Infrequently used, specific disease states
• Glucocorticoids – sarcoidosis, excess vitamin D
• Cinacalcet – primary hyperparathyroidism, lithium
•
•
•
•
associated hypercalcemia
Denosumab – refractory to bisphosphonates
Ketoconazole – sarcoidosis
Hydroxychloroquine – sarcoidosis
Gallium nitrate – multiple SEs
Pharmacotherapy: A Pathophysiologic Approach, 9e
Treatment – Other
• Severely impaired renal function  consider HD
• Patients with primary hyperparathyroidism or malignancy
may require surgery and or chemotherapy
• Review patient’s medications and diet!
• Hypercalcemia can increase risk of digoxin toxicity
• Restore upright posture and mobility
Pharmacotherapy: A Pathophysiologic Approach, 9e
Summary of Treatment
Best Pract Res Clin Endocrinol Metab. 2003; 17(4):623-51
Back to LC
• NS 2 L given in ED
• Na 122, K 3.4, SCr 2.25, Ca 14 (corrected 14.3), albumin 3.6, PTH 7
• Calcitonin 260 units SC given (1/21/14 @ 1815)
• Admit to medicine
• Per patient- no appetite past
week, took 20-30 tums daily for
abdominal pain  Diagnosed with
milk alkali syndrome
• Calcium carbonate and duloxetine
held
• Calcium continued to normalize
(10.5  9.3  9.1)
References
1.
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7.
8.
Maier JD, Levine SN. Hypercalcemia in the intensive care unit: a review of pathophysiology,
diagnosis, and modern therapy. Intensive Care Med. 2013; 00(0):1-18.
Weiss-Guillet EM, Takala J, Jakob SM. Diagnosis and management of electrolyte emergencies.
Best Pract Res Clin Endocrinol Metab. 2003; 17(4):623-51.
Barton Pai A. Chapter 35. Disorders of Calcium and Phosphorus Homeostasis. In: DiPiro JT,
Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic
Approach, 9e. New York, NY: McGraw-Hill; 2014.
Miacalcin injection [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals
Corporation; March 2014.
Zometa [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; April 2014.
Pamidronate Disodium [package insert]. Bedford, OH: Bedford Laboratories; October 2012.
Saunders Y, et al. Systematic review of bisphosphonates for hypercalcemia of malignancy.
Palliat Med. 2004;18(5):418-431.
Major P, et al. Zoledronic acid is superior to pamindronate in the treatment of hypercalcemia of
malignancy: a pooled analysis of two randomized controlled clinical trials. J Clin Oncol.
2001;19(2):558-567.