CONTENTS

• Signs & symptoms
• EKG findings
• Labs
• Etiology
• Investigation of cause
• Treatment
• Podcast
• Questions & discussion
• Pitfalls
• PDF of this chapter (or create customized PDF)

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signs & symptoms

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symptoms

• Neuromuscular excitation
  • Seizure (generalized tonic-clonic, generalized absence, or focal seizures)
  • Anxiety, delirium
  • Paresthesias (tingling around mouth, hands)
  • Muscle cramping, weakness, myalgias, laryngospasm
• Cardiovascular:
  • Hypotension (may be vasopressor-refractory)
  • Ventricular tachycardia (including Torsades de Pointes)
  • Heart block, Bradycardia

signs

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

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EKG findings

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Key finding:  the 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.
• You don't absolutely need an EKG to see this;  it may be observable on a monitor or on a rhythm strip.
• 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, but it generally shouldn't be checked daily as an “ICU routine.”

ionized calcium is what matters physiologically

• This is the best measurement of biologically active calcium in critically ill patients.
• The “normal” range (based on healthy people) is 1.1-1.3 mM, but most ICU patients tend to run below this range.
• Ionized calcium <0.8 mM probably warrants treatment (but there is no clear evidence that this improves outcomes).
• Ionized calcium <0.65 mM is critically low (may cause hypotension).

total calcium

• The normal range is 8.5-10.5 mg/dL (or 2.12-2.62 mM).
• This should be used as a screening test only.   Total calcium is not very accurate in critical illness (ionized calcium depends on a variety of factors, including pH, protein levels, sodium level, and phosphate level).
• Total calcium may be corrected for albumin, if albumin is readily available.
  • The corrected calcium is a bit better than uncorrected calcium, but still not very reliable.  pH abnormalities will affect the affinity of albumin for calcium, rendering this formula incorrect.
  • Calcium falls by ~0.8 mg/dL for every 1 g/dL reduction in serum albumin below 4.
  • Corrected Calcium (mg/dL) = Measured Calcium (mg/dL) + 0.8(4 – Albumin in g/dL)
  • Corrected calcium may be calculated using MDcalc here.

gadolinium-induced pseudohypocalcemia following contrast-enhanced MRI scan

• Some forms of gadolinium may falsely reduce calcium levels by interference with the assay (17043710).
  • Gadodiamide and gadoversetamide can do this.
  • Gadopentetate dimeglumine, gadoterate meglumine, gadoteridol don't seem to affect calcium measurement.
• Primarily, this is 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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causes of hypocalcemia

• Severe inflammation (sepsis, major burns)
• Pancreatitis (especially:  hypertriglyceridemic pancreatitis)
• Citrate (massive transfusion, plasmapheresis, leukapheresis, renal replacement therapy)
• Ethylene glycol poisoning
• Alkalosis
  • Respiratory alkalosis (e.g., panic-induced)
  • Metabolic alkalosis (e.g., sodium bicarbonate infusion)
• Electrolytic disarray (one electrolyte abnormality leading to subsequent abnormalities)
  • Magnesium abnormality (either hypo- or hyper-magnesemia).
  • Hyperphosphatemia of any etiology (e.g., renal failure, tumor lysis syndrome, rhabdomyolysis)

medications/intoxications

• Anticonvulsants (phenytoin, phenobarbital, carbamazepine)
• Strange antibiotics (INH, rifampin, pentamidine, aminoglycosides, amphotericin, foscarnet)
• Loop diuretics
• Inhibition of bone reabsorption (bisphosphonates, calcitonin, denosumab)
• Chemotherapy (cisplatin, 5-fluorouracil)
• Poisoning with hydrofluoric acid

chronic causes

• Hypoparathyroidism of any etiology (e.g. autoimmune, postoperative, cinacalcet)
• Vitamin D deficiency (e.g. poor intake, malabsorption)
• Osteoblastic metastases (e.g. prostate, breast CA)

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investigation of cause

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#1)  confirm hypocalcemia & obtain complete electrolyte panel

• Electrolytes, including calcium, magnesium, phosphate.
  • Hyperphosphatemia suggests:  rhabdomyolysis, tumor lysis, renal failure, or hypoparathyroidism.
• Ionized calcium, if not already obtained.

#2)  evaluate for etiology (if not clear based on history & examination) 

• Lipase
• Creatinine kinase
• PTH
  • Should be elevated in response to hypocalcemia.
  • Low or inappropriately normal value is diagnostic for hyperparathyroidism.
• 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 a problem in activating vitamin D (e.g. renal failure, hypoparathyroidism).

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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:
  • (a) Symptoms (listed above).
  • (b) Prolonged QT interval, in the absence of other causes (e.g. hypokalemia or hypomagnesemia).
  • (c) Severe hypocalcemia?  (iCa < ~0.8 mM, although there is no good data regarding this cutoff).
• Contraindications/cautions:
  • Hyperphosphatemia:  If the phosphate is elevated, giving calcium may increase the (Calcium x Phosphate) product, causing precipitation of calcium phosphate (calciphylaxis).   The ideal treatment here is a phosphate binder and the treatment of any underlying cause.
  • Ethylene glycol poisoning:  In ethylene glycol intoxication, giving calcium may promote the precipitation of calcium oxalate in the brain.
  • Digoxin poisoning:  This might be a theoretical contraindication, but more recent evidence suggests that calcium administration is actually safe here (19201134).

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 total.   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.
• 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).
• Oral calcium
  • This may be used for mild hypocalcemia -or- transitioning patients off IV calcium.
  • Usual dose is calcium carbonate 1 gram q12hr.

other treatment considerations

• Magnesium abnormalities may exacerbate hypocalcemia (especially hypomagnesemia); these may require treatment.
  • Calcium abnormalities should resolve within minutes to hours following magnesium repletion (if this was the etiology).
• Treatment of any specific etiology of hypocalcemia (e.g. low vitamin D level) may be required.
  • Mild hypocalcemia plus hyperphosphatemia is generally being driven by the hyperphosphatemia.  Treatment should focus on management of the hyperphosphatemia (discussed in the chapter on hyperphosphatemia).

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podcast

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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.

Going further:

• Aberegg SK   Ionized calcium in the ICU: should it be measured and corrected?   Chest 2016; 149(3) 846-855  (Spoiler alert: Not really).
• Hypocalcemia (EMDocs, Anand Swaminathan)
• Hypocalcemia (LITFL, Chris Nickson)
• Hypocalcemia (WikEM)