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CALL US...TM
The Official
Newsletter of the
Volume
4, Number 4
Winter, 2006
The Use of Calcium in Toxicology
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·
Introduction ·
Case presentation ·
Epidemiology ·
Pathophysiology ·
Clinical presentation ·
Diagnosis ·
Treatment ·
Discuss case questions ·
Consultation assistance |
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.
Consultation assistance
Consultation with a specialist
in poison information or with a medical toxicologist can be obtained free of
charge by calling the California Poison Control System at 1-800-222-1222.
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