Hypercalcemia

Basics of Calcium Regulation & Hypercalcemia

• Calcium participates in various biochemical processes and is critical for heart function, bone strength, muscle contraction, and as a signaling molecule.¹
• Calcium is regulated by three key hormones including¹
  • Parathyroid hormone (PTH)
  • 1,25-dihydroxy Vitamin D3 (Vitamin D3)
  • Calcitonin
• When serum calcium levels decrease, the parathyroid glands secrete PTH, which restores calcium levels by stimulating osteoclast-mediated bone resorption, enhancing renal calcium absorption, and stimulating the kidneys to produce Vitamin D3 to promote absorption in the intestines (Figure 1).^1,2
• When serum calcium levels increase, calcitonin is released by the thyroid C cells to reduce calcium levels by inhibiting osteoclast activity, promoting calcium deposition into bone, and increasing excretion in urine (Figure 1).^1,2

Hypercalcemia

• The normal reference range for total serum calcium is 8.5 to 10.5 mg/dL.¹
• Calcium also exists in its ionized (biologically active) form, which ranges from 4.8 to 5.6 mg/dL.¹
• Values above these thresholds indicate hypercalcemia.
• Hypercalcemia can be classified by severity based on total serum calcium levels (Table 1).¹

Causes of Hypercalcemia

Diagnostic Laboratory Tests for Hypercalcemia

1. Serum Calcium

• Ionized calcium is the most accurate reflection of active calcium status.³
• Total calcium may require correction for albumin levels.³

2. Parathyroid Hormone

• Elevated PTH with high calcium suggests primary hyperparathyroidism.^1,3,4
• Suppressed PTH suggests non-PTH mediated hypercalcemia (e.g., malignancy, Vitamin D excess).^1,3

3. 24-hour Urinary Calcium and Calcium/Creatinine Clearance Ratio (UCCR)

• UCCR <0.01 → Suggests familial hypocalciuric hypercalcemia³
• UCCR >0.02 → Suggests primary hyperparathyroidism.³

4. Vitamin D (25(OH)D and 1,25(OH)2D)

• High 1,25(OH)2D with low PTH may point to sarcoidosis or lymphoma.³
• Vitamin D intoxication can also cause hypercalcemia.^1,3

5. PTH-related Peptide

• Elevated in humoral hypercalcemia of malignancy.^3,5

Common causes of hypercalcemia secondary to increased bone resorption, increased gastrointestinal absorption, and decreased renal clearance are listed in Tables 1-3.

Clinical Presentation of Hypercalcemia

• Clinical manifestations can range from asymptomatic to serious complications depending on the acuity and severity.
• Early symptoms are often nonspecific, including fatigue, muscle weakness, and common gastrointestinal complaints such as nausea, constipation, and abdominal pain.^1,4
• Altered mental status or lethargy may occur in severe cases.¹
• Bone pain/fractures may be present due to increased bone resorption.^1,4
• Renal calculi may develop.⁴
• On ECG, a shortened QT interval is the most characteristic finding.¹
  • Other changes, such as PR prolongation, widened QRS, or arrhythmias (bradycardia), can also be seen.^1,4

Treatment of Hypercalcemia

Initial Management

• IV hydration (0.9% saline):
  • First-line treatment is to correct volume depletion and promote urinary calcium excretion.⁶
• Initiation of calcium-lowering agents (Table 5):

Targeted Therapies

1. Parathyroidectomy

• Indicated for primary hyperparathyroidism in patients who meet surgical criteria, such as:
  • Serum calcium >1.0 mg/dL above normal^1,6
  • Osteoporosis or fragility fractures^1,6
  • Nephrolithiasis or hypercalciuria^1,6
  • Age <50^1,6

2. Cinacalcet

• Increases sensitivity of calcium-sensing receptors^1,4
• Used in primary hyperparathyroidism in patients who are not surgical candidates¹

3. Dialysis

• Considered in severe hypercalcemia with renal failure^1,4,6
  • Typically performed using a low or calcium-free dialysis solution¹

Anesthetic Considerations of Hypercalcemia

• Hypercalcemia can cause arrhythmias, hypertension, and bradycardia.^1,4
• Hypercalcemia causes volume depletion due to polyuria; therefore, perioperative rehydration with IV saline solution is an important initial step to restore volume imbalances.^1,8
• High calcium levels may blunt the effect of β-adrenergic inotropes like epinephrine and dobutamine by interfering with adenylate cyclase, which can reduce the inotropic response.⁸
  • Vasopressors that act independently of β-receptors, such as phenylephrine and amrinone, are usually unaffected.⁸
• In the setting of hypercalcemia, nondepolarizing muscle relaxants should be used with caution.⁸
  • Their duration of action is often prolonged, especially in the presence of muscle weakness, although shortened duration has been reported with atracurium.⁸
  • Starting with a lower initial dose, with subsequent titration, is recommended.⁸
• Volatile anesthetics may have less myocardial depressant effect in hypercalcemia, but caution is needed when used with calcium channel blockers.⁸
• Acidosis increases ionized calcium, and alkalosis reduces it by increasing protein-binding.
  • Therefore, careful pH management is required during surgery to avoid calcium fluctuations that may affect cardiac and neuromuscular function.⁸