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Acute Management Overview
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Initial treatment of a patient with acute CAS poisoning includes providing general care, (eg, GI decontamination, monitoring for dysrhythmias, measuring electrolyte and digoxin concentrations) and definitive care (eg, administering digoxin-specific antibody fragments). Secondary care includes treating complications such as dysrhythmias and electrolyte abnormalities.
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Gastrointestinal Decontamination
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The initial treatment should be directed toward prevention of further GI absorption. Rarely, if ever, should emesis or lavage may be considered because efficacy is limited due to rapid absorption from the gut and to the emetic effects of the drug itself. Patients with chronic ingestion also do not benefit from these GI decontamination techniques. Because many CASs, such as digitoxin and digoxin, are recirculated enterohepatically, both late and repeated activated charcoal administration (1 g/kg of body weight every 2–4 hours for up to 4 doses) are beneficial in reducing serum concentrations.17,21,67,71,86,121 Activated charcoal prevents reabsorption of CAS from the GI tract and reduces the serum half-life. It should be administered in CAS toxic patients if definitive therapy with digoxin-specific Fab is not immediately available or when renal function is inadequate.21,
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Digoxin-Specific Antibody Fragments.
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The definitive therapy for patients with life-threatening dysrhythmias from CAS toxicity (in descending order of associated mortality: ventricular tachycardia, AV junctional tachycardia, AV block127) is to administer digoxin-specific antibody fragments.2,34,36,87,90,97,106,112,125 Purified digoxin-specific Fab causes a sharp decrease in free serum digoxin concentrations; a concomitant, but clinically unimportant, massive increase in total serum digoxin concentration; an increase in renal clearance of CAS (as a bound drug); and a decrease in the serum potassium concentration.2 In addition, the administration of digoxin-specific Fab is pharmacoeconomically advantageous.22 Although the antidote itself is relatively expensive, its expense is far outweighed by obviating the need, risk, and expense of long-term intensive care unit stays and of repetitive evaluation of potassium and digoxin concentrations. Table 65–4 lists the indications for administering digoxin-specific Fab. Extensive discussion is found in Antidotes in Depth: A19.
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Other Cardiac Therapeutics.
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Secondary treatments used in patients with symptomatic CAS exposures include the use of atropine for supraventricular bradydysrhythmias or high degrees of AV block. Atropine dosing is 0.5 mg administered IV to an adult or 0.02 mg/kg with a minimum of 0.1 mg to a child. Atropine should be titrated to block the vagotonic effects of CASs. The dose may be repeated at 5-minute intervals if necessary. Therapeutic success is unpredictable because the depressant actions of CASs are mediated only partly through the vagus nerve.
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Phenytoin and lidocaine are rarely used (secondary to Fab fragments obviating their utility) for the management of CAS-induced ventricular tachydysrhythmias and ventricular irritability. These xenobiotics depress the enhanced ventricular automaticity without significantly slowing, and perhaps enhancing, AV nodal conduction.96 In fact, phenytoin may reverse digitalis-induced prolongation of AV nodal conduction while suppressing digitalis-induced ectopic tachydysrhythmia without diminishing myocardial contractile forces.48 In addition, phenytoin may terminate supraventricular dysrhythmias induced by digitalis more effectively than lidocaine.96 Underlying atrial fibrillation and flutter typically do not convert to a normal sinus rhythm with administration of phenytoin or lidocaine. When used, phenytoin should be slowly IV infused (~ 50 mg/min) or in boluses of 100 mg repeated every 5 minutes until control of the dysrhythmias is achieved or a maximum of 1000 mg has been given in adults or 15 to 20 mg/kg in children.9,80 Fosphenytoin has not been evaluated in this setting. Maintenance PO doses of phenytoin (300–400 mg/day in adults and 6–10 mg/kg/day in children) should be continued until digoxin toxicity is resolved. Lidocaine is given as a 1- to 1.5-mg/kg IV bolus followed by continuous infusion at 1 to 4 mg/min in adults, or as a 1- to 1.5-mg/kg IV bolus followed by 30 to 50 μg/kg/min in children as required to control the rhythm disturbance (Chap. 64).
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Class IA antidysrhythmics are contraindicated in the setting of CAS poisoning because they may induce or worsen AV nodal block and decrease His-Purkinje conduction at slow heart rates and because their α-adrenergic receptor blockade and vagal inhibition may induce significant hypotension and tachycardia. Class IA antidysrhythmics are also prodysrhythmogenic, and their safety in the setting of CAS poisoning is unstudied. Additionally, quinidine reduces renal clearance of digoxin and digitoxin. The use of isoproterenol should be avoided in CAS-induced conduction disturbances because there may be an increased incidence of ventricular ectopic activity in the presence of toxic concentrations of CAS.
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Pacemakers and Cardioversion
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External or transvenous pacemakers have had limited indications in the management of patients with CAS poisoning. In one retrospective study of 92 digitalis-poisoned patients, 51 patients were treated with cardiac pacing, digoxin-specific Fab, or both; the overall mortality rate was 13%.113 Prevention of life-threatening dysrhythmias failed in 8% of patients treated with immunotherapy and 23% of patients treated with internal pacemakers. The main reasons for failure of digoxin-specific Fab were pacing-induced dysrhythmias and delayed or insufficient doses of digoxin-specific Fab. Iatrogenic complications of pacing occurred in 36% of patients. Thus, overdrive suppression with a temporary transvenous pacemaker should not be used in the presence of CAS poisoning.6,113 In the setting of digoxin poisoning, administration of transthoracic electrical cardioversion for atrial tachydysrhythmias is associated with the development of potentially lethal ventricular dysrhythmias. The dysrhythmias were related to the degree of toxicity and the amount of administered current in cardioversion.99 Transthoracic pacing may be attempted for atropine unresponsive bradydysrhythmias in settings where definitive care (digoxin-specific Fab fragments) are delayed or unavailable. In CAS-poisoned patients with unstable rhythms, such as unstable ventricular tachycardia or ventricular fibrillation, cardioversion, and defibrillation, respectively, are indicated.
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Hypokalemia and hyperkalemia may exacerbate CAS cardiotoxicity even at “therapeutic” digoxin concentrations. When hypokalemia is noted in conjunction with tachydysrhythmias or bradydysrhythmias, potassium replacement should be administered with serial monitoring of the serum potassium concentration. Digoxin-specific Fab administration generally should be withheld until the hypokalemia is corrected as the life-threatening manifestations of CAS cardiotoxicity may resolve.
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Hyperkalemia may also exacerbate CAS-induced cardiotoxicity, at “therapeutic” digoxin concentrations. Reduction in potassium concentrations should be judiciously initiated with care to avoid hypokalemia. Any exacerbation of CAS cardiotoxicity despite this correction should be treated immediately with Fab fragments.
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In acute CAS toxicity, if potassium is at least 5 mEq/L, digoxin-specific antibody fragments are indicated. If digoxin-specific Fab is not available immediately, and ECG evidence of a dysrhythmia suggestions of hyperkalemia is present, an attempt should be made to lower the serum potassium with IV insulin, dextrose, sodium bicarbonate, and PO administration of the ion-exchange resin sodium polystyrene sulfonate as indicated. Caution should be applied to the subsequent administration of digoxin-specific Fab because of concern for profound hypokalemia.
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Although calcium is beneficial in most hyperkalemic patients, in the setting of CAS poisoning, administration of calcium salts is considered to be potentially dangerous. A number of experimental studies cite the additive or synergistic actions of calcium and CAS on the heart (because intracellular hypercalcemia is already present), resulting in dysrhythmias,37,83,104 cardiac dysfunction61 (eg, hypercontractility, so-called “stone heart,” hypocontractility), and cardiac arrest.72,104,119 Although a 2004 study was unable to show an adverse effect,43 there exist three case reports8,64 of CAS-poisoned patients who died at various intervals after calcium administration, which supports the withholding of calcium administration in the setting of hyperkalemia induced by CAS poisoning.
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The purported mechanism is augmented intracellular cytoplasmic Ca2+, which results from an increased transmembrane concentration gradient that further inhibits calcium extrusion through the Na+-Ca2+ exchange or increased intracytoplasmic stores.59 This additional cytoplasmic calcium may result in altered contraction of myofibril organelles,61 less negative intracellular resting potential that allows delayed afterdepolarizations to reach firing threshold,47,59,83 altered function of the sarcoplasmic reticulum,61,95 or increased calcium interfering with myocardial mitochondrial function (Chaps. 16 and 17).61 Although some investigators suspect that the rate of administration of the calcium may be a factor in the subsequent cardiac toxicity,72,83 calcium administration should be avoided because better, safer, alternative treatments, such as digoxin-specific Fab, insulin, and sodium bicarbonate, are available for CAS-induced hyperkalemia.8,37,64,83,104
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Hypomagnesemia may also occur in CAS-poisoned patients secondary to the contributory factors mentioned with hypokalemia, such as long-term diuretic use to treat congestive heart failure. The theoretical benefits of magnesium therapy in the setting of hypomagnesemia include blockade of the transient inward calcium current, antagonism of calcium at intracellular binding sites, decreased CAS-related ventricular irritability, and blockade of potassium egress from CAS-poisoned cells.4,31,55,89,100,110,122 Although hypomagnesemia increases myocardial digoxin uptake and decreases cellular Na+-K+-ATPase activity, there is conflicting evidence as whether magnesium “reactivates” the CAS-bound Na+-K+-ATPase activity.81,100,110
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A common regimen uses 2 g of magnesium sulfate IV over 20 minutes in adults (25–50 mg/kg/dose to a maximum of 2 g in children). After stabilization, adult patients with severe hypomagnesemia may require a magnesium infusion of 1 to 2 g/h (25–50 mg/kg/h to a maximum of 2 g in children), with serial monitoring of serum magnesium concentrations, telemetry, respiratory rate (observing for bradypnea), deep tendon reflexes (observing for hyporeflexia), and monitoring of blood pressure. Magnesium is contraindicated in the setting of bradycardia or AV block, preexisting hypermagnesemia, and renal insufficiency or failure.
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Extracorporal Removal of Cardioactive Steroids
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Forced diuresis,66 hemoperfusion,77,79,120 and hemodialysis120 are ineffective in enhancing the elimination of digoxin because of its large volume of distribution (4–10 L/kg), which makes it relatively inaccessible to these techniques. Because of its high affinity for tissue proteins, approximately 10% of the amount of digoxin is found in the serum than is found at the tissue level, and of that amount, approximately 20% to 40% is protein bound.57