A29: Antidotes in Depth

Calcium is essential to maintain the normal function of the heart, vascular smooth muscle, skeletal system, and the nervous system. It is vital in enzymatic reactions, in neurohormonal transmission, and in the maintenance of cellular integrity.²¹ The endocrine system maintains calcium homeostasis. Approximately half of the total serum calcium is ionized and active, and the remainder is primarily bound to albumin. Hypercalcemia raises the threshold for nerve and muscle excitation, resulting in muscle weakness, lethargy, cardiac conduction disturbances, and coma.²¹ Hypocalcemia can result in hyperreflexia, muscle spasms, tetany, seizures, and QT interval prolongation (Chaps. 16 and 19).²¹

Early evidence suggested that in hypocalcemic children,¹⁰ intravenous (IV) infusions of calcium chloride produce slightly larger increases in ionic calcium than infusions of calcium gluconate, but this concept has been challenged.^43,70 Administration of equivalent molar doses of calcium found in calcium chloride (1 g CaCl₂10%) and calcium gluconate (3 g Ca gluconate 10%) produce similar serum ionized calcium concentrations, with both peaks occurring within 30 seconds in a model utilizing the anhepatic stage of liver transplant.⁴³ These results support the concept that simple dissociation of calcium from gluconate is responsible for releasing calcium, rather than hepatic metabolism.

Calcium enters cells in numerous ways. In cardiac and smooth muscles the voltage-dependent L-type channels are inhibited by the calcium channel blockers (CCBs) available in the United States.^5,60 Patients with CCB overdose (Chap. 61) may develop nausea, vomiting, hypotension, bradycardia, myocardial depression, sinus arrest, atrioventricular (AV) block, and metabolic acidosis with hyperglycemia, shock, pulmonary edema, altered mental status, and seizures.⁵⁰ Because CCBs do not alter either receptor-operated channels or the release of calcium from intracellular stores,⁶⁵ the serum calcium concentration remains normal in overdose.

IV administration of calcium to dogs poisoned with verapamil or diltiazem improves cardiac output secondary to increased inotropy.²⁵ The heart rate and cardiac conduction are affected minimally, if at all.^22,25,56 Case reports and reviews of the literature suggest similar findings in humans.^{2,3,11,17,20,26,31,34,41,53,54,62}

Calcium should be administered to symptomatic patients with CCB overdoses.^30,37,40 Unfortunately, the most seriously ill patients respond inadequately, and other measures are often required. The dose of calcium needed to treat patients with CCB overdose is unknown. In animal experiments, there appears to be a dose-related improvement.^11,25 Since calcium chloride is extremely irritating to small vessels, subcutaneous tissue, and muscle, and may cause necrosis following extravasation, it is usually only administered through a central venous line. The customary approach is to administer an initial IV dose of 3 g of calcium gluconate (30 mL of 10% calcium gluconate) or 1 g of calcium chloride (10 mL of 10% calcium chloride) to adults.⁵⁰ Based on case reports, this dose may need to be repeated as clinically indicated. The hypothesis is that sufficient calcium must be present to compete with the CCB for binding to the L-type calcium channel. One author used a total of 10 g of calcium gluconate as 1 g boluses over 12 minutes after diltiazem induced asystole and another 2.5 g of calcium gluconate minutes later for a second asystolic event, with a resultant serum calcium concentration of 13.44 mg/dL (normal: 8.4–10.2 mg/dL) approximately 1 hour after administration of the calcium gluconate.³² Several authors have successfully treated patients with a total of 18 to 30 g of calcium gluconate or 13 g of calcium chloride over 2 to 12 hours, either by intermittent bolus dose or infusion, without apparent adverse effects.^{11,30,31,37,40,41} However, following the use of large doses of calcium, hypercalcemia can occur and is associated with severe consequences including myocardial depression and intense vasoconstriction leading to multiorgan ischemia.⁶⁰ Introduction of hyperinsulinemia euglycemia (Antidotes in Depth: A17) and intravenous fat emulsion (Antidotes in Depth: A20) in the treatment of CCB overdose has diminished the need for extensive calcium administration. The provision of massive calcium doses should be limited, and if used, meticulous monitoring of ionized calcium is advised to avoid hypercalcemia (Table A29–1).

The administration of calcium to a patient with toxicity from cardioactive steroids such as digoxin might prove harmful.^24,69 In the event of concurrent overdose with both a cardioactive steroid and a CCB, the early use of digoxin-specific antibody fragments (Antidotes in Depth: A19) should enable the subsequent safe use of calcium (Chap. 65).

Therapy in children is based on more limited data. The American Heart Association pediatric guidelines suggest an initial dose of 20 mg/kg of 10% calcium chloride (0.2 mL/kg), not to exceed the adult dose.¹ This is infused over 5 to 10 minutes, preferably into a central venous line. If a beneficial effect is observed, an infusion of 20 to 50 mg/kg/h follows. These guidelines preferentially suggest calcium chloride based on the study mentioned above that compared the chloride to the gluconate salt in critically ill children with hypocalcemia.¹⁰ However, since CaCl₂ may be irritating, calcium gluconate may be preferable, especially if central venous access is unavailable. The starting dose in children should be 60 mg/kg of 10% calcium gluconate (0.6 mL/kg), not to exceed the adult dose.

In vitro studies suggest that the negative inotropic action of β-adrenergic antagonists are related to interference with both the forward and reverse transport of calcium in the sarcoplasmic reticulum and the inhibition of microsomal and mitochondrial calcium uptake (Chap. 62).^18,38,48 In a canine model of propranolol poisoning, the administration of calcium chloride improved mean arterial pressure, the change in maximal left ventricular pressure over time, and peripheral vascular resistance, but it had no significant effect on bradycardia or QRS complex prolongation.³⁹ Several case reports attest to the beneficial effects of IV calcium in β-adrenergic antagonist overdose.^9,33,52,57 Because distinguishing an overdose of a CCB from that of a β-adrenergic antagonist may be difficult and the two may be taken simultaneously, a trial of IV calcium is appropriate for a presumed β-adrenergic antagonist overdose if cardioactive steroid toxicity can be excluded.

Following ethylene glycol poisoning (Chap. 109) metabolism of the parent molecule generates oxalic acid, which complexes with calcium and subsequently precipitates in the kidneys, brain, and elsewhere, resulting in hypocalcemia.^{2,31,49,60,63} After exposure to ethylene glycol, the ionized calcium concentration should always be monitored, along with repeated examinations for signs of hypocalcemia such as QT interval prolongation, hyperreflexia, muscle spasms, tetany, and seizures (Chap. 19). IV calcium should be administered in the customary recommended doses (as above) to patients with these findings.

Deaths from dermal, gastrointestinal, and pulmonary hydrofluoric acid (HF) exposures are well documented in the literature.^13,23,68 In these cases, hypocalcemia is invariably present. Any body contact with HF (Chap. 107) can result in severe burns and death, depending on concentration, area exposed, and duration of exposure. The toxicity results from (a) release of free hydrogen ions; (b) complexation of fluoride with calcium and magnesium to form insoluble salts, which cause cellular necrosis; (c) liberation of potassium ions; and (d) cellular dehydration.^12,19,42,44 Soluble salts of fluoride and bifluoride (eg, sodium, potassium, and ammonium) have all the toxicity associated with HF and should be managed accordingly. Following HF exposure, the gluconate salt of calcium is used topically and subcutaneously to manage minor to moderate cutaneous burns, intravenously to treat systemic hypocalcemia, and intraarterially to manage significant burns.^{2,12, 13, and 14,16,19,23,42,44,47,51,55,58,66,67,72} Experimental studies demonstrate that when concentrated HF burns are immediately flushed with water and then treated with topical calcium, burn size is significantly reduced.⁸ Management of HF burns with a topical dimethyl sulfoxide (DMSO)–calcium gluconate combination seems promising, but a randomized clinical trial has yet to be published.²⁷ Although a DMSO preparation is not commercially available, a 2.5% calcium gluconate topical gel is marketed. In the event that the commercial preparation is inaccessible, a topical calcium gel can be prepared from calcium carbonate tablets, calcium gluconate powder or solution, and a water-soluble jelly such as K-Y Jelly (mix 3.5 g calcium gluconate powder or 35 mL of a 10% calcium gluconate solution or 10 g of calcium carbonate tablets or seven 500 mg crushed calcium gluconate tablets with 5 ounces of K-Y Jelly). An experimental study in rats demonstrated that iontophoretic delivery of calcium chloride appeared to enhance the delivery of calcium and to significantly reduce the burn area if applied within 30 minutes, and this may be a promising modality in the future.^56,71

The chloride salt is also acceptable for topical therapy. However, calcium chloride should never be injected into tissues (subcutaneously, intramuscularly), since severe tissue necrosis can result.

In patients with severe topical HF exposures, aggressive administration of regional IV calcium using a Bier block technique (10 mL of 10% ­calcium gluconate in a total volume of 40 mL) or intraarterial calcium (10 mL of 10% calcium gluconate in 50 mL (total volume) of 5% dextrose solution over 4 hours) may be required, along with frequent serum calcium determinations to titrate the dose.^27,64 One patient who was massively exposed to HF required a total of 267 mEq of calcium infused over a 24 hour period.²³

In patients with life-threatening poisoning and particularly HF inhalation, simultaneous administration of IV, oral, and nebulized 2.5% calcium gluconate can be given to facilitate the availability of the maximum amount of calcium. To prepare nebulized calcium gluconate, mix 1.5 mL of 10% calcium gluconate solution with 4.5 mL of sterile water or 0.9% sodium chloride to make a 2.5% solution. For moderate to severe burns (generally from HF concentrations >10%) of the fingers and hands, an intraarterial calcium infusion may be more effective than local or IV therapy, although it is more invasive^{51,58,64,66,67} and more hazardous.⁵⁸ A calcium gluconate solution (10 mL of 10%) mixed in 40 to 50 mL of 5% dextrose solution can be infused intraarterially over 4 hours followed by subsequent 40 to 50 mL intraarterial infusions after 4 hours when pain persists.⁶⁶ Serum calcium, potassium, and magnesium concentrations should be carefully monitored in all severely poisoned patients.

Hypocalcemia from the ingestion of household fluoride-containing dental products (eg, dental fluoride rinses, sodium fluoride tablets) rarely occurs and is dose dependent. Hypocalcemia and significant morbidity and mortality occur with ingestion of industrial strength fluoride cleaners or ­fluoride releasers (eg, ammonium bifluoride used for cleaning white wall tires). Patients with these exposures should be treated with calcium in a manner similar to the hypocalcemia from other causes.

Inappropriate use of oral and rectal phosphates, as a laxative can result in hypocalcemia, hyperphosphatemia, and hyperkalemia with resultant morbidity and mortality.⁴ IV calcium may be needed for life threatening hypocalcemia. However, since administration of calcium in the presence of hyperphosphatemia risks precipitation of calcium phosphate throughout the body, hemodialysis and other therapies should be considered in non–life-threatening cases.

Hypermagnesemia causes both direct and indirect depression of skeletal muscle, resulting in neuromuscular blockade, loss of reflexes, and profound muscular paralysis, with attendant ventilatory failure (Chap. 19).^36,46 Excess magnesium also causes prolongation of the PR interval and QRS complex on electrocardiography (ECG) and depression of the sinoatrial node, leading to a bradycardic arrest. IV calcium serves as a physiologic antagonist to these adverse effects of magnesium (Table A29–1).

Hyperkalemia causes significant myocardial depression. The resultant ECG changes are well defined. The height of the T wave increases and lengthening of the PR interval and QRS complex occur; ultimately, a sine wave pattern precipitating cardiac arrest may occur (Chaps. 16 and 19).²¹ Calcium makes the membrane threshold potential less negative, restoring the resting and threshold potential difference so that a larger stimulus is required to depolarize the cell from the resting potential. This stabilization antagonizes the hyperexcitability caused by modest hyperkalemia. However, when severe hyperkalemia exists, voltage-gated sodium channels are inactivated and cannot be depolarized, regardless of the strength of the impulse. Calcium may transform the voltage sensor of the sodium channel from inactive to closed, thus allowing the sodium channel to be opened with depolarization.²⁹ If hyperkalemia is secondary to the toxic effects of cardioactive steroids on the Na⁺-K⁺-adenosine triphosphatase (ATPase) pump, IV calcium can potentially exacerbate an already excessive intracellular calcium concentration, making IV calcium potentially harmful (Chap. 65).²¹

Severe hypercalcemia is defined by a serum calcium concentration greater than 14.0 mg/dL (3.5 mmol/L) in a patient with a normal albumin concentration. The adverse effects of hypercalcemia (independent of the rate of administration) include nausea, vomiting, constipation, ileus, hypertension if intravascular volume is adequate, polyuria, polydipsia, cognitive difficulties, hyporeflexia, coma, and enhanced sensitivity to cardioactive steroids.⁶ Significant hypercalcemia may lead to myocardial depression. The symptoms exhibited depend on the patient's age, rate of increase in the serum calcium concentration, and duration of the hypercalcemia.⁶

Neither calcium chloride nor calcium gluconate should be combined and administered intravenously with sodium bicarbonate because calcium carbonate, a precipitate, is formed. Calcium chloride is an acidifying salt and is extremely irritating to tissue. It should never be given intramuscularly, subcutaneously, or perivascularly.^21,45 Calcium gluconate is less irritating, but care should also be taken to avoid extravasation. The best reason for choosing calcium gluconate in almost all clinical situations is that the tissue risk is far less. If extravasation should occur, subcutaneous injection of aliquots of hyaluronidase can be injected around the site (Special Considerations: SC4).

Calcium injection is in Food and Drug Administration pregnancy category C. Animal reproduction studies have not been conducted. Benefit is expected to outweigh risk when indicated as life saving therapy for the mother. Calcium is excreted in breast milk but is likely safe.

IV calcium must be administered slowly, at a rate not exceeding 0.7 to 1.8 mEq/min or one 10 mL vial of calcium chloride or three 10 mL vials of calcium gluconate over 10 minutes in adults, unless the patient is in extremis. More rapid administration may lead to vasodilation, hypotension, bradycardia, dysrhythmias, syncope, and cardiac arrest.^{7,15,35,45,61} In cases of life threatening hypocalcemia or for a patient in extremis, a slow IV push may be required. Repeat doses may be administered as clinically indicated. Total and ionized calcium should be monitored.

Topical, nebulized, and intraarterial administration is specifically addressed in the section on the role of calcium in the management of HF.

A variety of calcium salts are available for parenteral administration. The two most commonly used are calcium chloride (10%) and calcium ­gluconate (10%) (Table A29–1).

A topical calcium gluconate gel (Calgonate) (2.5%) 25 g is available. Topical preparations can be extemporaneously made as described in the section on role in hypocalcemia secondary to HF. A commercially prepared calcium gluconate 1% solution (Calgonate emergency eyewash) is available in 120 mL squirt bottles.

• IV calcium infusion is an effective antidote for the hypocalcemia induced by ethylene glycol, HF, and fluoride releasing xenobiotics.

• Equivalent molar calcium doses found in appropriate volumes of calcium gluconate and calcium chloride deliver equal amounts of ionized calcium.

• Calcium serves as a physiologic antagonist to the cardiac and or neurologic effects of hypermagnesemia and hyperkalemia and counteracts some of the effects of CCB overdoses.

• Calcium may have some benefit in the treatment of β-adrenergic antagonist overdoses.

• Great care must be taken to avoid extravasation, as calcium chloride in particular can cause tissue necrosis.

• ECG monitoring and frequent ionized calcium concentration measurements are required to prevent iatrogenic toxicity.

• Although most clinical experience involves IV use, advances in intraarterial, topical, inhalational, and intraosseous calcium therapy may offer unique potential advantages.

References