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CALL US...TM
The Official Newsletter of the California
Volume 7, Number 1
Spring 2009
NOVEL ANTIDOTES
IN CALCIUM CHANNEL ANTAGONIST TOXICITY: CHICKEN SOUP FOR THE TOXIC HEART
INTRODUCTION
As the
CASE PRESENTATION
A 17-year-old
female presented three hours after taking at least ten of her grandmother’s sustained-release
verapamil 200 mg tablets. She presented to an emergency
department, lethargic with a systolic blood pressure of 80 mm/Hg and a regular
weak pulse of 56 bpm. Her pupils were 3 mm equal and reactive
bilaterally. The bedside glucose was 340
mg/dl. She was placed on a cardiac monitor
and an ECG obtained that showed a narrow bradycardic
rhythm at a rate of 52, but with no consistent P waves with the ventricular
complexes: she was in third degree heart block.
As per ACLS algorithm, she was given atropine 2 mg IV and placed on an external
pacemaker. An ampoule of 10% calcium gluconate was infused IV.
None of these treatments resulted in an improvement in blood pressure. A second ampoule of 10% calcium gluconate was infused without improved hemodynamic
status. Poison Control was contacted for
further treatment recommendations.
QUESTIONS
- What is the initial approach to
stabilization and decontamination of a potentially lethal CCA overdose?
- What are the mechanisms for CCA
toxicity?
- What other antidotes are
available to treat calcium channel antagonist toxicity?
Epidemiology
Calcium
channel antagonists in overdose are among the most dangerous cardiovascular
drugs. Over 10,000 exposures were reported
to the American Association of Poison Control Centers in 2008 regarding these
agents, 74 of which resulted in major toxicity, with an additional 17 resulting
in death. In fact, just one nifedipine capsule has resulted in the death of a 14 month old child
in spite of aggressive care .
PATHOPHYSIOLOGY
Calcium
channel antagonists cause cardiovascular collapse through blockage of calcium
channels. In the heart, such channels
are responsible both for excitation-contraction coupling and generation of the
action potential in the sino-atrial node. This combination results in CCAs being both
negative inotropic and chronotropic
agents. Additional insult comes from the
necessity of calcium in maintaining peripheral vascular tone. Peripheral blockade of calcium channel
channels interferes with vasoconstriction, further contributing to hypotension.
More recent
data shows that CCAs are also metabolic poisons. The heart is typically dependent on free
fatty acids for energy. In CCA toxicity,
as in other forms of cardiovascular stress, the heart becomes more dependent on
carbohydrates for energy. Unfortunately, in spite of increased need, insulin
release from the pancreas is blocked by CCAs, thereby exacerbating the ability
of the heart to use the preferred energy substrate efficiently. The end result is hypodynamic
cardiac function.
CLINICAL PRESENTATION
The hallmark
of CCA toxicity is hypotension with bradycardia. This bradycardia
can develop into various forms of heart block, including sinus arrest with a
ventricular escape rhythm. Moderate
ingestions, particularly of the dihyrdropyridines
(e.g. nifedipine, amlodipine)
may actually cause reflexive tachycardia early in the poisoning in response to
peripheral vasodilatation.
Additional
clinical manifestations of CCA toxicity include metabolic acidosis and altered
mental status commensurate with the degree of shock. Because of the diabetic effect of CCAs, there
usually is some hyperglycemia. Extreme
cases may be accompanied by seizures or pulmonary edema.
DIAGNOSIS
There are no
readily available laboratory drug levels for CCAs. The differential diagnosis for bradycardia and hypotension associated with poisoning includes
beta blockers; clonidine; organic phosphorus and carbamate pesticides; and cardiac glycosides such as digitalis
and digoxin.
Typically in acute digoxin toxicity, serum potassium
will be elevated with normoglycemia. Except for digoxin,
most hospital labs can not provide timely levels of any of these agents. Because poisoning by CCAs causes inhibition
of insulin secretion, another clue to the diagnosis may be the presence of
hyperglycemia, however the absence of this finding does not definitely exclude
the diagnosis.
Investigation
of the heart using an electrocardiogram may confirm the ingestion of CCAs. On
ECG there is usually bradycardia with variable
degrees of heart block. The bedside
ultrasound may show decreased cardiac contractility.
TREATMENT
Initial approach
For patients
with bradycardia and hypotension, intravenous saline
and atropine are good initial approaches.
An epinephrine infusion may be started, but this often has variable
effect. If the patient presents soon
after the ingestion (within an hour) or the ingestion involves a sustained
release preparation, then administration of activated charcoal may be
useful. However,
attention to the airway and avoidance of aspiration takes precedence.
Adding whole bowel irrigation with polyethylene glycol solution may be useful for
gastrointestinal decontamination in overdose of sustained-release
preparations.
Specific antidotes
The initial
antidote for CCA toxicity has traditionally been calcium bolus and infusion. Given either in a peripheral vein as calcium gluconate, or centrally as calcium chloride, these agents may
competitively reverse some of the calcium channel blockade. A minimum of three
to five 10 ml ampoules of 10% calcium gluconate (0.6
ml/kg), or 1-3 of 10% calcium chloride should be tried initially. The goal is a doubling of the ionized calcium
level to 2-3 meq/L or targeting a
corrected serum calcium of 15-18 meq/L. If the there is a response in blood pressure
or heart rate, then a continuous infusion of calcium gluconate
10%, 1.0 ml/kg/hr (calcium chloride 10%
0.3 ml/kg/hr) may be started. Although
calcium chloride is theoretically superior to the gluconate
form because three times more free calcium is available, there should be
caution in administering the chloride form peripherally, because of the danger
of extravasation and tissue necrosis. Calcium chloride is preferably administered
via central vascular access.
Glucagon,
although more traditionally used in beta blocker toxicity, may also have a role
in CCA toxicity. Bypassing both calcium
and beta receptor in myocytes, glucagon has an
independent pathway that stimulates adenyl cyclase in the cell.
This results in positive inotropic and chronotropic effects.
In dog models of verapamil toxicity, glucagon
works as well as catecholamines and calcium. It is typically given at an initial dose of 2
to 10 mg (50 to 150 mcg/kg) for an adult. This can be followed by an infusion of 0.05
to 0.1 mg/kg/hr. One should be cautious in patients with hypotension and
altered mental status because of the issue of aspiration from glucagon-induced
vomiting.
Newer treatments
The most
vexing issue with CCA toxicity is that it often does not respond to traditional
ACLS intervention. In one series of CCA intoxicated
patients, less than half of them responded to atropine, cardiac pacing or isoproterenol. In addition, many cases still fail to
respond even with the addition of calcium and glucagon. Recent animal models of verapamil
toxicity show promise with metabolic interventions, namely insulin and lipid
emulsion.
Insulin-Euglycemia
Because CCAs
are metabolic poisons in the heart, insulin was tested as an inotropic agent. With inhibition of pancreatic function,
exogenous insulin allows the heart to utilize carbohydrates more efficiently,
thereby helping to reverse the shock state.
Multiple animal studies attest to its efficacy, showing superiority of
insulin over catecholamines, glucagon and even calcium. In addition, multiple case series comprising
over 60 patients in refractory shock from CCAs show its ability to act as a
rescue agent when routine treatment was not working.
Because of
insulin resistance and hyperglycemia, CCA toxic patients can tolerate high
doses of insulin. The typical starting dose for regular insulin is a bolus of 1
IU/kg, followed by an infusion of 0.5 IU/kg/hr.
Also, a bolus or 25 gm of dextrose is given initially, followed by an infusion
of 0.5 gm/kg/hr. Regular glucose
monitoring is done hourly to avoid hypoglycemia, which has been reported in 20%
of cases treated in this fashion. If a dire case warrants insulin infusion,
then it should be started early because there is usually a delay of an hour in onset
of its effect.
Intravenous Lipid Emulsion
Another new
metabolic therapy that can be used in addition to or in place of insulin in
refractory CCA toxicity cases is intravenous lipid emulsion. Intravenous lipid
emulsion (ILE) was discovered years ago to reverse cardio toxicity in rats and
later dogs from bupivicaine, a long acting
anesthetic. Although there are no randomized human trials to date, there are
multiple case reports, including patients with cardiac arrest after bupivicaine, that have recovered after ILE with minimal or
no neurological sequelae.
Intravenous
lipid emulsion has since been shown to be possibly useful in other cardiotoxins. As opposed to the traditional antidote of
sodium bicarbonate in tricyclic antidepressant
toxicity, ILE was essentially 100% protective in a lethal rabbit model of clomipramine toxicity.
An impressive lethal rat study of verapamil
toxicity showed improved survival time and increased median lethal dose with
the use of ILE. Recently, a patient with
cardiac arrest from an acute ingestion of bupropion
and lamotrigine showed return of spontaneous
circulation after almost an hour of CPR, responding within minutes to the
infusion of 100 ml of 20% Intralipid ®.
Intravenous
lipid emulsion therapy is readily available in most hospitals for hyperalimentation.
Known as Intralipid ®, it consists mainly of
soybean oil (20%) and egg yolk phospholipids (2.25%) emulsified in glycerin and
water. Although
hospital charges seem often random and inflated, currently a pack of ten 100 ml
Intralipid 20% containers lists at $240.80 (Baxter
Product Catalog, 2007) – relatively inexpensive for a potential life saving
agent.
Whenever one considers a new antidote,
potential risks must be weighed as well.
Intravenous lipid emulsion does have a boxed warning regarding neonatal
use because of the risk of fat overload syndrome with respiratory demise.
In adults at the doses recommended above, this is highly unlikely and
has not been reported in this scenario.
The manufacturer also recommends cautious use
in acute pancreatitis. Although
theoretically an allergic reaction to the soy or egg component could occur, hypersentitivity reactions to this agent are rare.
Lipids have
been postulated to have various mechanisms in reversing drug-induced cardiac
toxicity. These agents may simply
function as a lipid sink, extracting or sequestering lipophilic
drugs intravascularly, thereby making them less
available to cardiac tissue. In
addition, they may act as a metabolic antidote. Calcium channel antagonists are
known to impair myocardial use of fatty acids, thereby shifting dependence to
less efficient carbohydrates. In such a
scenario, administration of free fatty acids actually can improve ischemic
myocardial function by shifting energy sources back to fatty acids. Finally, the free fatty acids may directly
reverse CCA toxicity by activating calcium channels in the heart.
When
confronted with a case of refractory shock from CCAs, or other cardiotoxins, the California Poison Control System may
recommend a starting dose of 100 ml rapid bolus of the 20% Intralipid®
formulation. In children, typically one would start with 1.5 ml/kg. If there is minimal or no response initially,
the bolus can be repeated twice every 5 min.
DISCUSSION OF CASE QUESTIONS
- What is the initial approach to
stabilization and decontamination of a potentially lethal CCA overdose?
Obviously
attention to airway is the primary concern.
Once that is secured, initial treatment of bradycardia
and hypotension may benefit from atropine or external pacing. Instillation of activated charcoal may be
useful in early or sustained release overdoses; with the latter also benefiting
from whole bowel irrigation.
- What are the mechanisms for CCA
toxicity?
CCAs cause
shock through their effect in lowering peripheral vascular resistance, cardiac
contractility and cardiac rate. The net effect is a hypotensive,
bradycardic patient.
In addition, CCAs are a metabolic poison, increasing cardiac dependence
on carbohydrates in the face of insulin resistance or deficiency.
- What other antidotes are
available to treat calcium channel antagonist toxicity?
The most
common antidotes are calcium and glucagon. If a bolus of either agent does not
have beneficial effect in reversing hypotension, one should quickly move to the
newer metabolic antidotes. Either a
bolus of insulin or intravenous lipid emulsion may be life-saving, provided
they are given early enough in severe cases.
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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