signs & symptoms
symptoms of hypercalcemia
- Delirium, which may progress to stupor and coma.
- Most relevant symptom with regard to ICU admission.
- Muscle weakness
- Abdominal pain, pancreatitis
- Constipation, ileus, nausea/vomiting
- Overall, hypercalcemia doesn't usually to have much impact on EKG or cardiac function.
- Short QT interval may be the most common and diagnostically useful finding.
- Other findings may include:
- Bundle branch block
- AV block with brady-asystolic arrest at extremely high levels.
- ST elevation may rarely be seen
Corrected calcium = Calcium + 0.8(4 – Albumin)
- Calcium is partially bound to albumin. This formula attempts to adjust the calcium level for changes in albumin.
- May be calculated at MDCalc here.
- Better than uncorrected calcium level, but not terrific (may tend to over-estimate calcium).
ionized calcium level
- Only ionized calcium is biologically active, so ionized calcium is the most clinically relevant measurement.
- If available, iCa should be used to manage hypercalcemia among critically ill patients.
more common causes
- Primary hyperparathyroidism (rarely causes severe hypercalcemia; diagnosis is suggested by chronic hypercalcemia)
- Adenoma (~90%)
- Diffuse hyperplasia (~10%)
- Carcinoma (~1%)
- Tertiary hyperparathyroidism (may be seen in end-stage renal disease)
- ~80%: Cancer produces protein that mimics PTH (PTH-related peptide).
- Most often squamous cell carcinoma of lung or head/neck.
- ~20%: Cancer invades bone directly (osteolytic metastases).
- Most often breast, lung, prostate, myeloma, or leukemia.
- Lymphoma (rogue hydroxylation, see purple box above).
- Vitamin A excess, all-trans retinoid acid (ATRA)
- Vitamin D excess, Calcitriol (1,25-OH vitamin D)
- Increased calcium intake:
- Milk-alkali syndrome
- In the context of chronic renal failure
- Teriparatide (an osteoporosis medication)
- Lithium or thiazide diuretics may exacerbate
- Parenteral nutrition (TPN) with excessive calcium
- Granulomatous disease (sarcoidosis, TB, fungal infections, Granulomatosis with Polyangiitis)
- Thyrotoxicosis (hypercalcemia is usually mild)
- Addison's disease
- Rhabdomyolysis recovery (rebound)
- Paget's disease
Overall, ~90% of hypercalcemia is due to primary hyperparathyroidism or malignancy. Among critically ill patients (especially with severe hypercalcemia), malignancy is the most likely cause.
- Complete electrolytes (including Ca/Mg/Phos)
- Hypophosphatemia suggests: hyperparathyroidism or humoral hypercalcemia of malignancy (due to PTH-related peptide)
- Hyperphosphatemia suggests: everything else (myriad disorders in which endogenous PTH is suppressed)
- ionized calcium level
- Elevated or inappropriately normal in primary or tertiary hyperparathyroidism
- Low in all other causes of hypercalcemia.
additional labs which may be considered:
- 25-OH vitamin D & 1,25-OH vitamin D
- Malignancy-related tests
- PTH-related peptide (PTH-rp)
- Serum protein electrophoresis (SPEP)
- Prostate specific antigen
- Skeletal survey
- Alkaline phosphatase (may be elevated in malignancy with bony metastases, without abnormality of other liver function tests)
- Mild-moderate hypercalcemia without symptoms doesn't require aggressive treatment (e.g. calcitonin, bisphosphonate).
#1 treat any identifiable cause
- Discontinue any potentially contributory medication (listed above).
- Treat any underlying diseases (e.g. rhabdomyolysis, hyperthyroidism, adrenal insufficiency).
- Immobility may exacerbate hypercalcemia, so patients should be mobilized if possible.
- Steroid is useful for selected causes of hypercalcemia (sarcoidosis, lymphoma). Low doses may be adequate (e.g. 20-40 mg prednisone daily).
- Hyperparathyroidism may be treated by calcimimetics (cinacalcet).
#2 volume resuscitation
- Hypercalcemia typically causes severe volume depletion (e.g. 3-6 liters) due to enhanced fluid excretion by the kidneys and reduced oral intake. This may cause renal insufficiency, impairing calcium excretion.
- Initial volume resuscitation to a euvolemic state is essential:
- The initial and most important goal is to resuscitate the patient to a euvolemic state.
- Bedside echocardiography may help confirm adequate fluid resuscitation.
- Infusion of fluid at a rate of ~150-250 ml/hr may be reasonable until the patient reaches euvolemia.
- Optimal fluid selection?
- Lactated Ringers is suboptimal because it contains calcium.
- Various fluids may be chosen to address pH abnormalities as shown above.
- Plasmalyte is a good choice in most patients, as this is a balanced crystalloid which doesn't contain calcium.
- Normal saline has traditionally been used, but this may be suboptimal due to causation of acidosis and possibly increased risk of renal injury. Notably, many patients with hypercalcemia will have pre-existing acidosis and renal dysfunction.
- Ongoing maintenance infusion of fluid?
- If the patient is producing urine and balancing their input/output, then an ongoing infusion of fluid may be beneficial.
- The key here is that the patient must respond to the fluid infusion with an equal output of urine. If the patient is retaining fluid (with an ongoing positive fluid balance), then continuing fluid infusion will cause volume overload. Fluid infusion must be stopped in this situation.
- A reasonable infusion choice might be plasmalyte at 100-150 ml/hour, with close observation to avoid volume overload.
- Forced diuresis (e.g. saline plus furosemide) hasn't been shown to be beneficial.
- The key is really just adequate volume resuscitation to achieve euvolemia.
- Given the effectiveness of other medications (especially bisphosphonates), being extremely aggressive with fluid and furosemide is more likely to cause harm than benefit.
- Calcitonin causes a temporary reduction in calcium (stops working after about two days).
- Works largely via reduction of bone calcium reabsorption (similar to bisphosphonates).
- This is an excellent agent to control calcium while awaiting for the bisphosphonate to take effect (typically both agents will be initiated simultaneously).
- Usual dose is 4 units/kg given subcutaneously Q12 hours.
- Can cause nausea, vomiting, and flushing.
#4 IV Bisphosphonate
- Bisphosphonates appear to work regardless of the etiology of hypercalcemia.
- All people normally have ongoing uptake and release of calcium from the bones.
- Bisphosphonates block calcium release from the bones, causing unidirectional calcium uptake by the bones (Maier 2015).
- Two contraindications to bisphosphonates:
- (1) Avoid bisphosphonates in hypercalcemia due to increased calcium intake (milk-alkali syndrome), because this should resolve without bisphosphonate therapy (27959601)
- (2) Caution is needed for pre-menopausal women, as bisphosophonates may become incorporated into bone and released during a subsequent pregnancy.
- Bisphosphonates take days to work, so they should be started early (generally simultaneously with volume resuscitation & calcitonin).
- Zoledronic acid 4 mg IV is more effective than palmidronate and is the preferred treatment.
- The main side-effect of concern is renal failure. The risk of inducing clinically significant renal failure from a single dose of zoledronic acid is very low. Nonetheless, among patients with severe pre-existing renal dysfunction, the following measures should be considered to reduce the risk of kidney injury:
- (a) Use a smaller dose (e.g. 3 mg), especially in smaller patients.
- (b) Infuse over a longer duration of time (e.g., 60 minutes).
- (c) Ensure that the patient is adequately volume resuscitated (see #2 above).
- (d) Avoid other nephrotoxic agents.
- A more common side-effect is a flu-like syndrome, which may be treated symptomatically.
#5 refractory hypercalcemia
- In renal failure, dialysis is an option.
- Denosumab is a monoclonal antibody that inhibits osteoclast formation and bone resorption. This may be considered in hypercalcemia refractory to bisphosphonates, especially due to malignancy.
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questions & discussion
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- The strategy of large-volume continuous saline infusions combined with furosemide hasn't been shown to be effective. The risks of this strategy (e.g. volume overload) generally outweigh any potential benefits.
- The usual mistake in hypercalcemia treatment is over-emphasis on furosemide/saline, with underutilization of calcitonin and bisphosphonates.
- Ordering a fluid infusion at an arbitrary rate for an indefinite duration is not the preferred approach. This fails to achieve euvolemia rapidly, and also runs the risk of eventually causing volume overload.