CONTENTS
- Rapid Reference 🚀
- Signs & symptoms
- Calcium and iCa levels
- Causes
- Evaluation
- Treatment overview
- Miscellaneous topics
- Podcast
- Questions & discussion
- Pitfalls
evaluation of hypercalcemia
- Ionized calcium level.
- Electrolytes including Mg/Phos.
- Parathyroid hormone (PTH).
- PTH-related peptide (PTHrp).
- 25-OH vitamin D and 1,25-OH vitamin D.
- Thyroid stimulating hormone (TSH).
management of symptomatic/severe hypercalcemia:
volume resuscitation 📖
- If hypovolemic, rapidly resuscitate with plasmalyte to target euvolemia.
- (There is no role for forced diuresis.)
calcitonin 📖
- 4 units/kg s.q. q12 hours.
- Calcitonin only works transiently, so it must be given simultaneously with a bisphosphonate.
IV bisphosphonate 📖
- Indicated for most cases of hypercalcemia, except:
- ⚠️ Milk-alkali syndrome. 📖
- ⚠️ Premenopausal women.
- Zoledronic acid is preferred:
- The usual dose is 4 mg IV, infused over 60 minutes (slow infusion improves safety).
- Dose-reduce in renal failure:
- GFR 50-60 ml/min: 3.5 mg
- GFR 40-49 ml/min: 3.3 mg
- GFR <39 ml/min: 3 mg
symptoms of hypercalcemia
- Neurologic:
- Delirium, which may progress to stupor and coma.
- Paresthesia.
- Muscle weakness, hyporeflexia.
- Gastrointestinal:
- Abdominal pain, pancreatitis.
- Constipation, ileus, nausea/vomiting.
- Renal:
- Diabetes insipidus (with polyuria and polydipsia).
- Hypertension (if the patient isn't hypovolemic).
EKG findings
- 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 bradyasystolic arrest at extremely high levels.
- ST elevation may rarely be seen.
ionized calcium level
- Only ionized calcium is biologically active, so ionized calcium is the most clinically relevant measurement.
- iCa is the preferred measurement of calcium among critically ill patients, if it is available.
⚠️ albumin-corrected calcium shouldn't be used
- Formulas exist to correct the calcium level for the effect of varying albumin levels.
- Evidence demonstrates that formulas actually perform worse than uncorrected calcium levels.(34197298)
malignancy (most common cause of severe hypercalcemia)
- Humoral (~80%): Cancer produces protein that mimics PTH (PTH-related peptide).
- Squamous cell carcinomas (lung, head/neck, esophagus, cervix, colon).
- Urothelial carcinomas (kidney, bladder).
- Breast, endometrial, and ovarian cancers.
- Rarely: pancreatic neuroendocrine tumors, Hodgkin and non-Hodgkin lymphomas.
- Local osteolytic (~20%): Cancer invades bone directly, causing extensive osteolytic metastases.
- Carcinoma of the breast, lung, or prostate.
- Myeloma, leukemia, lymphoma.
- 1,25-dihydroxyvitamin D-mediated (<1%): Rogue hydroxylation.
- Lymphoma.
- Ectopic hyperparathyroidism (<1%).
- Rare tumors may secrete ectopic PTH (e.g., neuroendocrine, ovarian cancers).
hyperparathyroidism
- Primary hyperparathyroidism (rarely causes severe hypercalcemia; diagnosis is suggested by chronic hypercalcemia).
- Adenoma (~90%).
- Diffuse hyperplasia (~10%).
- Carcinoma (~1%).
- Tertiary hyperparathyroidism (may occur in end-stage renal disease).
medications
- Vitamin A excess, all-trans retinoic acid (ATRA).
- Vitamin D excess (>2350 IU/day increases the risk of hypercalcemia by 50%).(36282253)
- Calcitriol (1,25-OH vitamin D).
- Increased calcium intake:
- In the context of chronic renal failure.
- 🥛 Milk-alkali syndrome. 📖
- Teriparatide (an osteoporosis medication).
- Rebound after denosumab discontinuation.
- Potentially contributory:
- Lithium.
- Thiazide diuretics.
- Theophylline.
- Parenteral nutrition (TPN) with excessive calcium.
granulomatous disease
- Autoimmune:
- Sarcoidosis, berylliosis, inflammatory bowel disease.
- GPA (granulomatosis with polyangiitis).
- Langerhans cell histiocytosis.
- Infectious:
- Tuberculosis.
- Fungal infections (histoplasmosis, coccidiomycosis, candidiasis, Pneumocystis jirovecii).
- Lymphoma (some).
miscellaneous
- Thyrotoxicosis (hypercalcemia is usually mild).
- Adrenal insufficiency.
- Rhabdomyolysis recovery (rebound).
- Paget's disease.
- Immobilization may exacerbate hypercalcemia.
- VIPoma.
Overall, ~90% of hypercalcemia is due to hyperparathyroidism or malignancy. Among critically ill patients (especially those with severe hypercalcemia), malignancy is the most likely cause.
basic hypercalcemia lab panel
- Ionized calcium level.
- Complete electrolytes (including Ca/Mg/Phos):
- Hypophosphatemia suggests: hyperparathyroidism, humoral hypercalcemia of malignancy (due to PTH-related peptide), or sometimes milk-alkali syndrome.(36282253)
- Hyperphosphatemia suggests: everything else (myriad disorders in which endogenous PTH is suppressed).
- Parathyroid hormone (PTH):
- Elevated or inappropriately normal in primary or tertiary hyperparathyroidism.
- Low in all other causes of hypercalcemia.
additional labs which may be considered:
- TSH (thyroid stimulating hormone).
- 25-OH vitamin D. Elevated 25-hydroxyvitamin D suggests vitamin D intoxication (usually with levels >100-150 ng/mL or >250-374 nM).(36282253)
- 1,25-OH vitamin D. Elevation usually suggests excess intake or ectopic production (most often sarcoidosis, hematologic malignancy, or infection). (36282253)
- 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).
[1] Basic interventions for any hypercalcemic patient:
- Volume resuscitation.
- Management of underlying causes, e.g.:
[2] For severe or symptomatic hypercalcemia, usually add:
- Calcitonin to rapidly reduce calcium.
- Bisphosphonate to maintain reduction in calcium level.
initial volume resuscitation is the most important intervention:
- 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.
- The initial and most important goal is to resuscitate the patient to a euvolemic state.
- Bedside echocardiography may help confirm adequate fluid resuscitation.
optimal fluid selection
- Plasmalyte is an excellent choice in most patients, since this is a balanced crystalloid that doesn't contain calcium.
- Normal saline has traditionally been used, but normal saline is often suboptimal because it causes acidosis (and many patients with hypercalcemia will have pre-existing acidosis).
- Lactated Ringers is suboptimal because it contains calcium. However, LR has a physiological concentration of calcium (1.35 mM), which will be lower than the patient's calcium concentration. Thus, LR will will not elevate the patient's calcium level, so LR remains safe to use in patients with hypercalcemia.
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 might be plasmalyte at 100-150 ml/hour, with close observation to avoid volume overload.
forced diuresis (e.g. saline plus furosemide)
- 🛑 This has not been shown to be beneficial.(18711156)
- 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 (it stops working after about two days).
- Calcitonin works largely via reduction of bone calcium reabsorption (similar to bisphosphonates). It also reduces renal calcium reabsorption.
- Calcitonin is an excellent agent to control calcium while waiting for the bisphosphonate to take effect (typically both agents will be initiated simultaneously).
- The usual dose is 4 units/kg given subcutaneously Q12 hours.
- Note that intranasal calcitonin is ineffective for hypercalcemia.(26763520)
- Intramuscular calcitonin is effective, but may be less comfortable.
- Calcitonin can cause nausea, vomiting, flushing, and injection site pain.
indications & contraindications
- 💡 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.(24130250)
- Bisphosphonates take days to work, so they should be started early (generally simultaneously with volume resuscitation & calcitonin). They are generally indicated as a component of therapy for severe and/or symptomatic hypercalcemia.
contraindications to bisphosphonates
- ⚠️ Avoid bisphosphonates in hypercalcemia due to increased calcium intake (milk-alkali syndrome 📖). This should resolve without bisphosphonate therapy.(27959601)
- ⚠️ Caution is needed for premenopausal women, as bisphosphonates may become incorporated into bone and released during a subsequent pregnancy.
- ⚠️ Renal failure (depending on the agent).
zoledronic acid 💊
- Zoledronic acid 4 mg IV is more effective than pamidronate and is the preferred treatment.(11208851)
- 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 pre-existing renal dysfunction, the following measures should be considered to reduce the risk of kidney injury:
- Other side-effects:
pamidronate 💊
- Pamidronate may be used if zoledronic acid is unavailable.
- The dose is 60-90 mg IV, infused over 2-6 hours.
- Pamidronate is contraindicated if GFR is <30 ml/min.(31826272)
denosumab 💊
- Denosumab is a monoclonal antibody that inhibits osteoclast formation and bone resorption. Its utility includes:
- Hypercalcemia refractory to bisphosphonates (including hypercalcemia due to malignancy or hyperparathyroidism).
- Patients with severe renal failure, as an alternative to bisphosphonate therapy.
- The usual dose is 120 mg s.q. once. However, for bisphosphonate-naive patients with moderate hypercalcemia (<14 mg/dL), 60 mg has been suggested as a more appropriate dose.(36282253)
- Side-effects may include hypocalcemia, hypophosphatemia, and rash.(36282253)
cinacalcet (sensipar™️) 💊
- Cinacalcet is a calcimimetic that binds to calcium-sensing receptors. This inhibits secretion of PTH (parathyroid hormone) and also reduces calcium reabsorption in the kidneys.
- Cinacalcet is utilized primarily as therapy for hyperparathyroidism. However, case reports have also described its use in refractory, non-PTH mediated hypercalcemia due to malignancy.(35417639)
- Oral administration of 30 mg/day initially. May increase to 90 mg four times daily as needed.
- Side effects: may cause nausea, vomiting, headache, fractures.
glucocorticoid
- Physiology: Glucocorticoids inhibit gastrointestinal calcium absorption, increase urinary calcium excretion, and inhibit 1-alpha hydroxylase activity.(35417639)
- Potential indications:
- Low to moderate doses may be adequate, depending on the severity of the hypercalcemia (e.g., 20-40 mg prednisone daily).(36282253)
- Effects may not be apparent for more than four days.(31826272)
- Ketoconazole is an alternative to glucocorticoid, which similarly inhibits 1-alpha hydroxylase activity.(35417639)
dialysis
- This is an option to remove calcium in severe renal failure (e.g., GFR <10-20 ml/min).
- Reduction in calcium may be transient.
pathophysiology
- Calcium is absorbed from the gut via two mechanisms:
- The primary mechanism of absorption is via a passive, paracellular process.
- Active transport process mediated by 1,25-dihydroxyvitamin D.
- Excessive ingestion of oral calcium will suppress PTH, causing reduced conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. However, patients may continue to absorb excessive amounts of calcium.
- Hypercalcemia induces diuresis, which may promote acute kidney injury (filtered calcium activates the calcium-sensing receptor in the medullary thick ascending limb of the nephron, inhibiting the Na-K-2Cl cotransporter). This may, in turn, exacerbate calcium accumulation.(26763520)
epidemiology
- Milk-alkali syndrome is now the third leading cause of hypercalcemia leading to hospital admission among patients without end-stage renal disease (following malignancy and primary hyperparathyroidism). Common scenarios include the following: (26763520)
- (#1) Calcium carbonate supplementation for treatment of osteoporosis (this may also be aggravated by vitamin D supplementation).
- 💡 Ask about calcium supplements, as these often won't be listed on the patient's medication list.
- (#2) Calcium carbonate therapy for patients with chronic kidney disease, which is used to minimize secondary hyperparathyroidism.
- (Historically, milk-alkali syndrome resulted from the use of antacids to treat peptic ulcer disease. However, the the advent of more modern therapies, this scenario has largely disappeared.)
diagnosis
- The initial diagnosis of milk-alkali syndrome is typically based upon a combination of:
- Alkalosis.
- Renal impairment.
- Ingestion of calcium and absorbable alkali. (Diagnosis is especially supported by a history of aggressively over-ingesting calcium.)
- Exclusion of other causes.
- Diagnosis is confirmed by resolution of hypercalcemia with basic supportive measures, and subsequent ongoing normocalcemia (following discontinuation of oral calcium).
management
- Management is similar to other patients with hypercalcemia, with the exception that bisphosphonates are unnecessary (and potentially harmful).
- Patients may actually be at risk of overshoot hypocalcemia after oral calcium is discontinued (as their body re-establishes homeostasis).(26763520)
- Any other coexisting causes of hypercalcemia should be identified and addressed (e.g., immobilization, various medications).
Follow us on iTunes
The Podcast Episode
Want to Download the Episode?
Right Click Here and Choose Save-As
To keep this page small and fast, questions & discussion about this post can be found on another page here.
- 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.
Guide to emoji hyperlinks
- = Link to online calculator.
- = Link to Medscape monograph about a drug.
- = Link to IBCC section about a drug.
- = Link to IBCC section covering that topic.
- = Link to FOAMed site with related information.
- = Link to supplemental media.
References
- 24130250 Maier JD, Levine SN. Hypercalcemia in the Intensive Care Unit: A Review of Pathophysiology, Diagnosis, and Modern Therapy. J Intensive Care Med. 2015 Jul;30(5):235-52. doi: 10.1177/0885066613507530 [PubMed]
- 26763520 Klingeman HM, Kearns AE. 69-Year-Old Woman With Confusion and Fatigue. Mayo Clin Proc. 2016 Jan;91(1):e1-6. doi: 10.1016/j.mayocp.2015.06.020 [PubMed]
- 27959601 Spital A. Case 24-2016: A Man with Malaise, Weakness, and Hypercalcemia. N Engl J Med. 2016 Nov 17;375(20):e43. doi: 10.1056/NEJMc1612624 [PubMed]
- 31826272 Asonitis N, Angelousi A, Zafeiris C, Lambrou GI, Dontas I, Kassi E. Diagnosis, Pathophysiology and Management of Hypercalcemia in Malignancy: A Review of the Literature. Horm Metab Res. 2019 Dec;51(12):770-778. doi: 10.1055/a-1049-0647 [PubMed]
- 34197298 Kenny CM, Murphy CE, Boyce DS, Ashley DM, Jahanmir J. Things We Do for No Reason™: Calculating a “Corrected Calcium” Level. J Hosp Med. 2021 Aug;16(8):499-501. doi: 10.12788/jhm.3619 [PubMed]
- 35417639 Guise TA, Wysolmerski JJ. Cancer-Associated Hypercalcemia. N Engl J Med. 2022 Apr 14;386(15):1443-1451. doi: 10.1056/NEJMcp2113128 [PubMed]
- 36282253 Walker MD, Shane E. Hypercalcemia: A Review. JAMA. 2022 Oct 25;328(16):1624-1636. doi: 10.1001/jama.2022.18331 [PubMed]