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The Use of Calcium in Toxicology

By Jennifer Hannum, MD

Introduction

Calcium is a cation necessary for the normal functioning of a variety of enzymes and organ systems, including muscle and nerve tissue. The normal ranges for serum calcium concentrations are 8.4-10.2 mg/dL for total calcium, and 1.12-1.23 mmol/L for ionized calcium. Hypocalcemia, inhibition of calcium efflux, or blockade of calcium’s effects may cause muscle cramps, tetany, and ventricular fibrillation. Antagonism of calcium-dependent channels in the myocardium results in hypotension, bradycardia and atrioventricular block. There are a variety of clinical scenarios and poisonings in which calcium can be used as antidotal therapy.

Case presentation

A 35 year old man was working in his garage when he spilled rust remover on his gloves. Upon removing them, he noted a small hole on the dorsal aspect of the thumb of the left glove. He immediately rinsed his hands with water. Two hours later, he noted severe pain in his left thumb with some erythema on the dorsal surface. Upon arrival to the emergency department, he was afebrile with pulse of 98/minute, respirations of 16/minute, and blood pressure of 130/70 mm/Hg. Physical examination revealed erythema and blanching of a 1 cm region on the distal tip of his left thumb. There were no lesions or puncture wounds. There was no fluctuance or drainage. There was no tenderness to palpation along the flexor tendon or at the interphalangeal joints. He had full range of motion of his thumb, although it was painful. A 2.5% calcium gluconate gel was prepared and placed in the thumb of a latex glove that was applied to the patient’s left hand. His pain resolved temporarily but returned approximately 20 minutes later. Calcium gluconate gel was reapplied and opioid analgesics were administered. Serum electrolytes including calcium were within normal limits. WBC count was normal. After several hours of observation in the emergency department, his pain resolved and there was no progression of skin findings. He was discharged with oral pain medications and referred for follow-up the next day with a hand surgeon.

Questions

  1. What are some indications for calcium therapy in poisoning?
  2. What role does topical calcium have for dermal hydrofluoric acid exposure?
  3. What are the potential adverse effects of calcium administration?

Epidemiology

There are a variety of indications for calcium treatment in the setting of poisoning. Intravenous calcium may be used to correct toxin-induced hypocalcemia (e.g. fluoride or ethylene glycol poisoning); to treat transfusion-related hypocalcemia (induced by the anticoagulant citrate); or to reverse hypotension and dysrhythmias associated with calcium channel antagonists. Symptomatic electrolyte abnormalities such as hyperkalemia and hypermagnesemia may also benefit from calcium administration.

Pathophysiology

The mechanisms of action of antidotal calcium vary by the nature of the poison. In calcium channel antagonist poisoning, L-type calcium channels in the cardiac and vascular smooth muscle are blocked, resulting in (1) impaired firing of the sinus node pacemaker, (2) decreased rate of conduction through the AV node, (3) decreased cardiac contractility, and (4) decreased vascular tone. Administration of intravenous calcium in this scenario increases the efflux of calcium through open channels by significantly raising serum calcium levels above normal. Calcium may reverse the negative inotropic effect of calcium channel antagonists; however, depressed automaticity and atrioventricular nodal conduction velocity and vasodilatation may not respond to calcium administration.

Calcium is also useful in counteracting agents such as hydrofluoric acid (HF) and ammonium bifluoride, which liberate calcium-binding fluoride ions. Fluoride ions are highly reactive in tissues, causing cellular destruction by binding calcium in cell membranes. Exogenously administered calcium increases available substrate to reactive fluoride anions, forming less reactive CaF2 salts, which are cleared by the kidneys. For dermal fluoride exposures, calcium can be administered (1) topically as a gel, or in solution, (2) subcutaneously, (3) intra-arterially, or (4) intravenously via Bier block. Nebulized calcium gluconate has also been used for inhalational fluoride solution exposures.

Ethylene glycol poisoning results in the production of oxalic acid, a potent calcium-complexing metabolite. Severe hypocalcemia may result, especially in young children. Treatment is rapid replacement with intravenous calcium.

Calcium can stabilize cardiac cell membranes in certain hyperkalemic states; however, calcium is relatively contraindicated in poisonings from cardiac glycosides such as digoxin, which often result in hyperkalemia secondary to inhibition of sodium/potassium ATPase or coexisting renal insufficiency and failure. It is reasonable to reserve calcium administration for life-threatening dysrhythmias in which persistent hyperkalemia appears to be the primary cause.

Clinical presentation

Hypocalcemic patients may present with neuromuscular and cardiovascular manifestations, including paresthesias, cramps, carpopedal spasm, laryngeal spasm, tetany, seizures, and life-threatening dysrhythmias. Clinical presentation of specific poisonings denotes the need for antidotal calcium. Calcium channel antagonist poisonings often present with hypotension, bradycardia, and hyperglycemia. Dermal exposures to hydrofluoric acid may result in pain, progressive redness, swelling, and in severe cases skin blanching. These findings may be delayed for several hours after exposure. Timing and extent of symptoms varies with acid concentration. Recognition of these signs and symptoms should prompt the use of calcium as an antidote. Digoxin-induced hyperkalemia should only be treated with exogenous calcium when other measures (including digoxin Fab fragments) have failed.

Diagnosis

Measurement of serum or ionized calcium can aid in the diagnosis of toxin-induced hypocalcemia from fluorides or ethylene glycol. Large-surface-area HF burns and severe systemic ethylene glycol poisonings have resulted in some of the lowest-documented serum calcium concentrations in the medical literature. Patients with a history of possible poisoning by ethylene glycol or HF, and presenting with neurologic manifestations such as tetany, paresthesias or convulsions, or dysrhythmias with a prolonged QT interval, should be evaluated for hypocalcemia. Immediate replacement is necessary. A positive Trousseau or Chvostek signs may suggest low serum or ionized calcium concentration; however, these physical findings are inconsistent, thus necessitating laboratory determination of serum calcium in all cases of suspected toxin-induced hypocalcemia.

Treatment

Two formulations of intravenous calcium are available, calcium chloride and calcium gluconate. In a 10% solution, calcium chloride contains nearly three times the amount of calcium (27.2 mg/ml of elemental calcium), than calcium gluconate (9 mg/ml of elemental calcium). Extravasation of calcium chloride may cause local irritation or necrosis, so it should not be used for subcutaneous, intradermal or intra-arterial injections. Calcium chloride should be administered through central venous access whenever possible.

For symptomatic hypocalcemia or hyperkalemia, give calcium gluconate, 10-20 ml (children, 0.2-0.3 mL/kg), or 10% calcium chloride, 5-10 mL (children, 0.1-0.2 mL/kg), slowly IV. Repeat as needed every 5-10 minutes. Similar doses can be used for calcium channel antagonist poisoning. High-dose calcium therapy has been administered effectively in cases of severe calcium channel antagonist overdose. Serum calcium concentrations of approximately 1.5 to 2 times normal have correlated with improved cardiac function. As much as 12 g of calcium chloride has been given over 2 hours in the setting of calcium channel antagonist poisoning without adverse effect from hypercalcemia (serum calcium of 23.8 mg/dl in one published report). Calcium may be administered as multiple boluses (e.g. 1 g every 10-20 minutes) or as a continuous infusion (e.g. 20-50 mg/kg/h).

For dermal hydrofluoric acid exposures, topical calcium gels of varying concentrations (2.5% to 33%) have been used with success. A 2.5% gel is prepared by combining 1 g of calcium gluconate per 40 g (approximately 40 mL) of water-soluble lubricant gel. A 32.5% gel is prepared by compounding a slurry of ten 650 mg calcium carbonate tablets in 20 mL of water-soluble lubricant gel. For exposures involving the hand or fingers, place the gel into a large surgical latex glove, to serve as an occlusive dressing and to optimize coverage. Topical calcium treatment provides significant relief when started within three hours after injury. When topical treatment fails, subcutaneous injection may be attempted. Inject 5-10% calcium gluconate SC intralesionally and peripherally (0.5-1 mL/cm2 of affected skin) using a 27-guage or smaller needle. This may be repeated two to three times in 1 to 2 hour intervals as needed. No more than 0.5 mL should be injected into each digit. Lidocaine may be added to the calcium solution if needed for subcutaneous injection. Alternatively, a Bier block technique can be used for regional intravenous administration of calcium gluconate. To administer a Bier block, establish distal IV access in the affected extremity (ex. dorsum of the hand). Exsanguinate the extremity by elevation for 5 minutes or by distal-to-proximal wrapping of the extremity with an Esmarch bandage. Inflate a blood pressure cuff to just above systolic blood pressure. The arm is then lowered (or the bandage is removed). With the cuff inflated, infuse 25–50 mL of a 2% calcium gluconate solution (10 mL of 10% calcium gluconate diluted with 40 mL of D5W) into the empty veins. After 20–25 minutes, slowly release the cuff over 3–5 minutes. This procedure may be repeated. Alternatively, an intra-arterial infusion may be administered with 10 mL of 10% calcium gluconate with 50 mL of D5W infused over 4 hours through a brachial or radial artery catheter. The patient should be monitored closely over the next 4–6 hours, and if pain recurs, a second infusion may be administered.

A calcium-containing antacid (calcium carbonate) may be administered after oral fluoride ingestion to complex fluoride ions. Nebulized 2.5% calcium gluconate has been reported for cases of inhalational HF exposure.

Discussion of case questions

  1. What are some indications for calcium therapy?
    Calcium is indicated for symptomatic hypocalcemia resulting from intoxication by fluoride, ethylene glycol, or the intravenous anticoagulant citrate; hydrofluoric acid exposure; hypotension in the setting of calcium antagonist overdose; and severe hyperkalemia with cardiac manifestations.
  2. What role does topical calcium have for dermal hydrofluoric acid exposure?
    Calcium complexes with the highly reactive fluoride ion that is released secondary to hydrofluoric acid exposure. Calcium diminishes the pain and tissue destruction caused by the fluoride ion. Calcium can also be used systemically to treat hypocalcemia or hyperkalemia that may result from severe hydrofluoric acid exposure.
  3. What are the adverse effects of calcium administration?
    Adverse effects include tissue irritation, particularly with the chloride salt. Extravasation of calcium chloride may cause mild local irritation to severe tissue necrosis requiring skin grafting. Hypercalcemia may occur, especially in patients with diminished renal function. Hypotension, bradycardia, syncope and cardiac dysrhythmias may result from rapid intravenous calcium administration. Constipation may be caused by orally administered calcium salts.