CONTENTS

• Signs & symptoms
• EKG findings
• Labs
• Etiology
• Investigation of cause
• Treatment
  • Intravenous calcium for refractory shock
• Podcast
• Questions & discussion
• Pitfalls

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signs & symptoms

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Clinical manifestations relate to both the magnitude and acuity of hypocalcemia. 

symptoms

• Neuromuscular excitation:
  • Anxiety, delirium, depression, coma.
  • Paresthesias (perioral & extremities).
  • Muscle cramping (tetany, laryngospasm), weakness, myalgias.
  • Seizure (generalized tonic-clonic, generalized absence, or focal seizures).
• Cardiovascular:
  • Hypotension, impaired contractility (may be vasopressor-refractory).
  • Torsades de pointes.
  • Heart block, bradycardia.

signs

• Hyperreflexia.
• Muscle fasciculations.
• Trousseau's sign is a test for latent tetany:
  • Inflate blood pressure cuff above the systolic pressure for up to three minutes.
  • Positive if patient develops spasm of hand (see video below).
  • Patients with profound hypocalcemia may display this spasm without application of a blood pressure cuff (which is known as tetany).

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EKG findings

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ST segment duration is inversely related to the ionized calcium level

• Hypocalcemia causes ST segment prolongation.
• This may be noticed as QT prolongation with a normal-sized T-wave.
  • This may be seen on the patient's monitor or on a rhythm strip (without a full EKG).
• Hypocalcemia may cause torsade de pointes.

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labs

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when should we check calcium levels?

• Calcium should be checked if there is clinical suspicion for hypocalcemia (e.g., massive transfusion, arrhythmia, seizure, general electrolytic disarray).
• Perhaps calcium is worth checking once on admission to the hospital.
• ⚠️ Otherwise, calcium should not be checked daily as an “ICU routine.” Critically ill patients often have mildly low calcium levels, so routinely checking calcium levels in the ICU leads to the detection of asymptomatic hypocalcemia.

total calcium is a screening test only

• 8.5-10.5 mg/dL (or 2.12-2.62 mM) is the normal range.
• Total calcium should only be used as a screening test. Total calcium is not an accurate predictor of ionized calcium (since ionized calcium depends on numerous factors including pH, albumin level, sodium level, and phosphate level).

🏆 ionized calcium is what matters physiologically

• iCal measures the biologically active calcium. This is the most accurate and preferred way to measure calcium.
• 1.1-1.3 mM is the normal range seen in healthy people, but most critically ill patients tend to run below this range.
• <0.8 mM probably warrants treatment (although there is no clear evidence that treatment improves outcomes).
• <0.65 mM is critically low (possibly causing hypotension).

⚠️ 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) 

gadolinium-induced pseudohypocalcemia following contrast-enhanced MRI scan

• Some forms of gadolinium may falsely reduce calcium levels due to interference with the assay.(17043710)
  • Gadodiamide and gadoversetamide can do this.
  • Gadopentetate dimeglumine, gadoterate meglumine, gadoteridol don't seem to affect calcium measurement.
• This is primarily an issue immediately after MRI scans, although gadolinium may persist longer in patients with renal dysfunction.
• The diagnosis of pseudohypocalcemia is based upon the combination of gadolinium exposure, hypocalcemia (which may be insanely extreme), and the lack of other signs/symptoms of hypocalcemia.

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etiology

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hypoparathyroidism

• Primary hypoparathyroidism.
• Secondary hypoparathyroidism.
  • Cinacalcet, etelcalcetide.
  • Post-parathyroidectomy and post-thyroidectomy.
  • Hungry bone syndrome (transient hypoparathyroidism following parathyroidectomy for hyperparathyroidism).
  • Post-parathyroid gland radiation.
  • Hypermagnesemia.

impaired vitamin D synthesis or action

• Inadequate vitamin D intake.
• Malabsorption (e.g., steatorrhea).
• Liver disease.
• Chronic kidney disease with secondary hyperparathyroidism.
• Hypomagnesemia.

calcium chelation / precipitation

• Hyperphosphatemia of any etiology, for example:
  • Renal failure.
  • Tumor lysis syndrome.
  • Rhabdomyolysis.
• Exogenous citrate:
  • Massive transfusion (especially if combined with hepatic/renal dysfunction).
  • Plasmapheresis, leukapheresis (fresh frozen plasma contains citrate).
  • Renal replacement therapy with citrate regional anticoagulation.
• Pancreatitis (may relate to systemic inflammation and release of free fatty acids).
• Poisoning:
  • Ethylene glycol poisoning. 📖
  • Hydrofluoric acid.

decreased bone turnover

• Hypothyroidism.
• Calcitonin.
• Bisphosphonates.
• Denosumab.
• Osteoblastic metastases (e.g. prostate, breast cancer, small cell lung cancer).

other causes 

• Sepsis/critical illness (e.g.., due to a variable combinations of impaired vitamin D activation, inflammatory cytokines, and elevated procalcitonin).
• Alkalosis may reduce the ionized calcium due to increased albumin binding:
  • Respiratory alkalosis (e.g., panic-induced).
  • Metabolic alkalosis (e.g., sodium bicarbonate infusion).
• Continuous renal replacement therapy may cause ongoing magnesium and calcium losses.
• Miscellaneous other medications:
  • Chemotherapy (cisplatin, 5-fluorouracil).
  • Anticonvulsants (phenytoin, phenobarbital, carbamazepine).
  • Antibiotics (INH, rifampin, pentamidine, aminoglycosides, amphotericin, foscarnet).
  • Loop diuretics.
  • Propofol.

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investigation of cause

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• Magnesium level: Either hypomagnesemia or hypermagnesemia may cause hypocalcemia, so any magnesium abnormality requires management.
• Phosphate level:
  • Hyperphosphatemia suggests rhabdomyolysis, tumor lysis, renal failure, or hypoparathyroidism.
  • Hypophosphatemia suggests vitamin D deficiency.
• PTH:
  • PTH should normally be elevated in response to hypocalcemia. This is seen in most etiologies of hypocalcemia.
  • Low or inappropriately normal value is diagnostic for hypoparathyroidism.
• Calcidiol (25-hydroxy vitamin D) and calcitriol (1,25-hydroxy vitamin D):
  • Low 25-OH vitamin D indicates vitamin D deficiency.
  • Disproportionately low 1,25-OH vitamin D indicates inadequate vitamin D activation (e.g., renal failure, hypoparathyroidism).
• Lipase (if abdominal pain or concern for pancreatitis).
• Creatinine kinase (if the phosphate and potassium levels are elevated, in a pattern suggestive of rhabdomyolysis).

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treatment

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is treatment indicated?

Most critically ill patients have mild-moderate hypocalcemia. Treatment usually isn't indicated.

indications for treatment:

• Symptomatic hypocalcemia (symptoms listed above 📖).
• Severe hypocalcemia (iCa below ~0.8 mM is generally regarded as meriting therapy – but there is no solid data regarding this cutoff).(Vincent 2023)

contraindications/cautions:

• ⚠️ Hyperphosphatemia: If the phosphate is elevated, giving calcium may increase the calcium-phosphate product, causing precipitation of calcium phosphate (calciphylaxis). The ideal treatment here is treatment of the hyperphosphatemia.
• ⚠️ Ethylene glycol poisoning: In ethylene glycol intoxication, giving calcium may promote the precipitation of calcium oxalate in the brain.

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treatment regimen

In severe hypocalcemia, IV calcium is used initially with transition to oral calcium. For mild hypocalcemia, oral calcium could be used for initial treatment.

IV loading dose

• 1 gram calcium chloride (if central access) or 2-3 grams calcium gluconate (via peripheral line). Either may be infused over 10-20 minutes. Both work equally fast, but calcium chloride can cause tissue necrosis if it extravasates.
• In severe situations (e.g., frank tetany or massive transfusion), this may need to be repeated with careful monitoring of clinical symptoms and iCa levels.
• Side-effects: Nausea, vomiting, hypertension, flushing, chest pain.
  • ⚠️ Infusing calcium too rapidly causes patients to feel awful.

IV maintenance doses

• Calcium levels often fall after the initial IV dose, especially if there is a process causing ongoing calcium loss (e.g., pancreatitis).
• Additional smaller doses may be needed (e.g. 1 gram calcium gluconate over 60 minutes, repeated q1hr PRN).
• In very unusual situations with profound and ongoing hypocalcemia (e.g., hungry bone syndrome), scheduled IV calcium doses or a continuous infusion may be utilized.

oral calcium

• This may be used for mild hypocalcemia -or- transitioning patients off IV calcium.
• A reasonable dose is calcium carbonate 💊 1 gram q12hr (may escalate to 1 gram q6hr if needed).

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other treatment considerations: address any etiology

• Magnesium abnormalities may exacerbate hypocalcemia (especially hypomagnesemia); these may require treatment.
  • ⚠️ Maintaining an adequate calcium level may be impossible until hypomagnesemia is treated adequately (similar to how hypomagnesemia causes persistent hypokalemia).
• Hyperphosphatemia is a common cause of hypocalcemia. Treatment in this situation should always focus on management of the underlying hyperphosphatemia. 📖
• Vitamin D deficiency is an indication for supplementation. Oral calcitriol 💊 at 0.25-1 mcg/day may be especially helpful in some cases. (33542868)

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intravenous calcium for refractory shock

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[1] candidates for calcium infusion

• [1] Shock that is poorly responsive to conventional therapies.
• [2] iCa < ~0.8 mM.
• [3] Theoretically, impaired systolic heart function might correlate with the greatest benefit. (Alternatively, for patients with refractory vasodilatory shock and preserved systolic function, a vasoconstrictor such as methylene blue might be preferable.)

[2] loading/test dose

• Possible doses:
  • ~1 gram of calcium chloride. (29329694 recs 1-2 grams CaCl2)
  • ~2-3 grams of calcium gluconate.
• Hemodynamics should improve substantially. If there isn't hemodynamic improvement, additional calcium administration is probably unhelpful.

[3] continuous infusion

• Calcium gluconate at ~1 gram/hour seems to be a reasonable initial dose.
  • If the hospital doesn't have an order set for a continuous calcium infusion, this may be achieved by serially repeating doses of IV calcium administered as a slow infusion (e.g., 3 grams calcium gluconate infused over four hours, repeated continuously q4hrs).
  • Calcium gluconate may be preferred since this is safe either peripherally or centrally (in case central access is lost, limited, or unavailable). If calcium chloride is utilized, it should be administered via a central line with the dose reduced by a factor of three (e.g., 1/3 gram calcium chloride per hour).
• Check iCa level q4-6 hours (depending on illness severity).
• Target iCa level?
  • ~0.9-1.0 mM might be a reasonable rough target range.
  • If the patient is improving clinically and the iCa is 0.8-0.9, the calcium infusion may be continued without any up-titration.
  • It's probably unwise to target complete normalization of calcium (1.1-1.3 mM).

(evidentiary basis)

• Hypocalcemia can cause impaired myocardial contractility that can be vasopressor-refractory. Consequently, calcium repletion may be a rational therapy for patients with refractory shock.
• There is no high-quality evidence regarding the use of intravenous calcium for refractory shock in humans. In rats with endotoxic shock, calcium administration has been shown to increase mortality (whereas reduction of ionized calcium to 0.9 mM appeared to improve mortality). (2504540, 1423913) 

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Hypocalcemia is extremely common among critically ill patients. Inflammation in critical illness often causes mild-moderate hypocalcemia (e.g., ionized calcium >0.8 mM). This usually doesn't have clinical consequences and shouldn't be “repleted.”
• Routine daily monitoring of iCa in all ICU patients is a foolish and wasteful practice which needs to be abandoned.
• Calcium should be monitored and aggressively administered during massive transfusion.

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