Got Calcium?

Humble calcium may be an old standby, but we’re still finding novel uses for this abundant mineral, including treatment for acid burns.

Calcium is the most abundant mineral in the body. It provides structural integrity to the skeletal system and is essential in countless physiologic processes including contraction of cardiac, skeletal, and smooth muscle, nerve conduction, neurotransmitter and hormone release, activation of enzymatic reactions, and blood coagulation [1]. We commonly use calcium in the ED for treatment of hyperkalemia, but it is also useful in a variety of other conditions, like severe hypocalcemia, calcium-channel blocker overdose, and hydrofluoric acid burns. Here we will highlight the indications for calcium and review the important differences between the two commonly used forms: calcium gluconate and calcium chloride.

The Great Debate: Calcium Chloride or Calcium Gluconate?
Calcium can be given intravenously as a solution of either calcium gluconate or calcium chloride. A solution of calcium chloride, by virtue of a smaller molecular size, provides approximately three times as much elemental calcium compared to an equivalent mass of a calcium gluconate. Specifically, 1 gram of calcium chloride (1 ampule or 10 mL of a 10% calcium chloride solution) contains approximately 272 mg of elemental calcium compared to 92 mg of elemental calcium in 1 gram calcium gluconate (1 ampule or 10 mL of 10% solution) [^2,3].

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Although calcium chloride contains more calcium ions per gram, it is not without issue. Calcium chloride is a vesicant, and tissue necrosis is a well-documented side effect when it extravasates from veins. For this reason, some experts recommend calcium chloride should only be given through a central vein.

In spite of this extravasation risk, calcium chloride was traditionally recommended over calcium gluconate due to superior bioavailability, since the latter was thought to require first pass metabolism in the liver [4]. Thus, for a patient in cardiac arrest with hemodynamic instability or underlying liver disease, calcium chloride was preferred, since calcium ions would theoretically be instantly available rather than requiring liver metabolism.

However, more recent studies have debunked this myth of superior bioavailability of calcium chloride. In one study of patients being prepped for liver transplant, essentially having no functional liver tissue, equimolar amounts of calcium chloride (10mg/kg) and calcium gluconate (30 mg/kg) were administered for hypocalcemia that developed as part of the procedure. After 10 minutes, there was no difference in measured ionized calcium between the two groups. The authors concluded hepatic metabolism was not required for activation of calcium gluconate [5]. Another study compared calcium gluconate to calcium chloride for the treatment of hypocalcemia in children and found that the calcium concentration increased equally over a similar time frame, regardless of which formulation was used [6].

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The bottom line is that calcium gluconate appears to work just as well as calcium chloride and does not carry the same extravasation risk. For this reason, calcium gluconate is preferred, though it should be dosed at roughly two to three times the dose of calcium chloride. Calcium chloride should only be administered into central veins. However, the literature does support the emergent use of calcium chloride through a large peripheral vein in life-threatening situations when calcium gluconate is not available [4].

Life-Threatening Hyperkalemia
The most common reason we use calcium in the ED is for the treatment of severe hyperkalemia. Potassium is a primarily intracellular ion, and the gradient between intracellular and extracellular potassium is the most important determinant of the membrane resting potential of cardiac myocytes [7]. By affecting this gradient, hyperkalemia causes profound electrophysiological derangements, initially leading to cardiac excitability and ultimately impairing cardiac conduction, leading to ventricular fibrillation and asystole. By helping to restore the difference between resting and threshold membrane potentials, calcium antagonizes these effects to stabilize the cardiac membrane [^7,8].

In a hemodynamically unstable patient with suspected hyperkalemia, treatment should not be delayed to wait for the potassium level to result. Patients should be treated empirically with calcium because of the high risk of rhythm deterioration and cardiovascular collapse. For more stable patients, guidelines do not specify an absolute potassium threshold that should prompt treatment. Serious manifestations of hyperkalemia, such as cardiac arrhythmias, typically begin when serum potassium level rises above 7.0 mEq/L, or at lower levels with a very acute rise in serum potassium [9]. Most experts agree that individuals with potassium levels greater than 6.5 mEq/L or any EKG changes, including peaked T waves or prolonged intervals, should be treated promptly with calcium to stabilize the cardiac membrane, in addition to potassium-lowering therapy [7]. While calcium acts quickly to stabilize the cardiac membrane, effects are temporary, and repeat calcium dosing may be required.

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Calcium should also be administered to patients in cardiac arrest in which hyperkalemia or hypermagnesemia is suspected. Of note, ACLS guidelines do not recommend calcium for all cardiac arrests, owing to absence of benefit when given routinely [^2,3]. However, if hyperkalemia is the cause of the cardiac arrest, calcium can be life-saving and may lead to immediate return of spontaneous circulation. The dose of calcium for life-threatening hyperkalemia depends on the calcium salt selected: for calcium chloride, 1 g IV over 2-5 minutes; for calcium gluconate, 2-3g IV over 2-5 minutes [^2,3].

Hypocalcemia
Hypocalcemia can be seen with primary or acquired hypoparathyroidism, severe hypomagnesemia, and vitamin D deficiency and is caused by numerous drugs. Patients with mild hypocalcemia are often asymptomatic and can be treated with oral calcium replacement. Patients that have symptoms of hypocalcemia should receive IV calcium. Perioral numbness and carpopedal spasm usually appear first, and symptoms may progress to tetany, confusion, and seizures. QT prolongation caused by hypocalcemia can also lead to ventricular dysrhythmias.1 The dose of calcium gluconate for patients with moderate to severe hypocalcemia (<4 mg/dL) but no seizures or tetany is 4 mg IV over 4 hours. For patients with seizures or tetany, the dose is 1-2 g IV calcium gluconate over 10 minutes, repeating every 60 minutes until symptoms resolve [3]. In order to adequately correct calcium levels, any associated hypomagnesemia should also be corrected [1].

Calcium Channel Blocker Overdose
Calcium channel blocker overdose causes hypotension by directly inhibiting calcium influx into myocardial and vascular smooth muscle cells [^10]. Intravenous calcium can be used to overcome these cardiovascular effects. However, treatment with calcium alone is often insufficient and other treatments such as glucagon, vasopressors, high-dose insulin/glucose, and fat emulsion therapy may also be required. The dose of calcium gluconate is 60 mg/kg over 5 to 10 minutes, repeating every 10-20 minutes as needed for 3 to 4 additional doses. An infusion of 60 to 150 mg/kg/hr may also be used, titrated to improved blood pressure and contractility. The goal should be an ionized serum calcium level twice the reference range [3]. For calcium chloride, the dose is 1 to 2 g IV over 5 minutes, repeating every 10 to 20 minutes. Once a favorable response is obtained, consider IV infusion of 20 to 50 mg/kg/hr titrated to hemodynamics [2].

Hydrofluoric Acid Burns
An interesting role for calcium is in the treatment of hydrofluoric acid burns. In addition to copious water irrigation, calcium gluconate 2.5% gel can be applied to the burned area. If the burn is on the hand, the gel can be put in a surgical glove, which is then placed on the patient’s hand. Calcium ions in the gel binds to the free fluoride ions to form nontoxic calcium fluoride, leading to pain relief and preventing further tissue damage. If pain persists despite this topical treatment, 5% calcium gluconate solution can be injected subcutaneously (0.5 mL per square cm of wound area) in and around the affected area [^11]. Calcium chloride should never be given subcutaneously, so it should NOT be substituted for calcium gluconate. Another option is to infuse calcium gluconate via an artery or vein supplying the affected area. Consultation with a local poison control center or toxicologist is recommended prior to using this treatment.

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Managing Extravasation
Extravasation of calcium chloride, and to a lesser extent calcium gluconate, can result in severe local tissue injury, necrosis, and skin sloughing. If extravasation occurs, the infusion should be stopped and the line disconnected. A syringe can be used to try to gently aspirate any solution remaining in the catheter. The affected limb should be elevated and the patient observed. If symptoms develop, hyaluronidase can be injected into the area of injury. Inject a series of five 0.2 to 0.3 mL injections into the area infiltrated by the drug, moving in a clockwise fashion [2]. Hyaluronidase breaks down the hyaluronic acid in connective tissue, allowing dispersion, dilution, and ultimately absorption of the infiltrated drug [^12].

Cautions
Avoid rapid IV administration, which can result in bradyarrythmias or even asystole. Use with caution in patients with severe hyperphosphatemia, as it may result in precipitation of calcium phosphate [^2,3]. Manufacturer guidelines cite digoxin toxicity as a contraindication to use of calcium due to a theoretical risk of inducing cardiac tetany, or “stone heart.” However, the data behind this is poor, and this dogma has been called into question. A 2011 retrospective case review of 161 patients with digoxin toxicity found no increased risk of arrhythmias or death among those treated with intravenous calcium [¹³]. Nonetheless, it is prudent to use caution when administering calcium to patients who may have digoxin toxicity.

Pregnancy Considerations
There is no data on human or animal pregnancy studies for calcium gluconate or calcium chloride, and both drugs have been classified as pregnancy category C. In emergent situations such as cardiac arrest, lifesaving medications should not be withheld due to concerns of possible teratogenicity to the fetus [^14].

Cost

• Calcium chloride, 10% solution:
  10 mL : $10.24
• Calcium gluconate, 10% solution:
  100 mL: $21.04

REFERENCES

1. Chang W-TW, Radin B, McCurdy MT. Calcium, Magnesium, and Phosphate Abnormalities in the Emergency Department. Emerg Med Clin North Am. 2014;32(2):349-366. doi:10.1016/j.emc.2013.12.006.
2. Lexicomp: Calcium chloride: Drug information. www.uptodate.com. Accessed September 6, 2017.
3. Lexicomp: Calcium gluconate: Drug information.
4. Emergency physicians monthly: the calcium quandry. https://epmonthly.wpengine.com/article/the-calcium-quandary/. Accessed September 1, 2017.
5. Martin TJ, Kang Y, Robertson KM, Virji MA, Marquez JM. Ionization and hemodynamic effects of calcium chloride and calcium gluconate in the absence of hepatic function. Anesthesiology. 1990;73(1):62-65. http://www.ncbi.nlm.nih.gov/pubmed/2360741. Accessed September 7, 2017.
6. Cote’ CJ, Drop LJ, Daniels AL, Hoaglin DC. Calcium chloride versus calcium gluconate: comparison of ionization and cardiovascular effects in children and dogs. Anesthesiology. 1987;66(4):465-470. http://www.ncbi.nlm.nih.gov/pubmed/3565811.
7. Weisberg LS. Management of severe hyperkalemia. Crit Care Med. 2008;36(12):3246-3251. doi:10.1097/CCM.0b013e31818f222b.
8. Parham WA, Mehdirad AA, Biermann KM, Fredman CS. Hyperkalemia revisited. Texas Hear Inst J. 2006.
9. Mount D. Clinical manifestations of hyperkalemia in adults – UpToDate. https://www-uptodate-com.libproxy.lib.unc.edu/contents/clinical-manifestations-of-hyperkalemia-in-adults?source=search_result&search=hyperkalemia&selectedTitle=3~150. Accessed September 7, 2017.
10. Graudins A, Lee HM, Druda D. Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies. Br J Clin Pharmacol. 2016;81(3):453-461. doi:10.1111/bcp.12763.
11. Kaushik S, Bird S. Topical chemical burns-UpToDate. UptoDate.
12. Ann L, Patel S. Extravasation of Noncytotoxic Drugs: A review of the literature. Ann Pharmacother. 2014;48(7):870-886. doi:10.1177/1060028014527820.
13. Levine M, Nikkanen H, Pallin DJ. The Effects of Intravenous Calcium in Patients with Digoxin Toxicity. J Emerg Med. 2011;40(1):41-46. doi:10.1016/j.jemermed.2008.09.027.
14. Jeejeebhoy FM, Zelop CM, Lipman S, et al. Cardiac Arrest in Pregnancy. Circulation. 2015;132(18):1747-1773. doi:10.1161/CIR.0000000000000300.